Griseofulvin compound and pharmaceutical use thereof

ABSTRACT

The present invention addresses the problem of providing a compound for prophylaxis and/or treatment of central inflammatory diseases, or a pharmacologically acceptable salt thereof. The present invention addresses a compound of a general formula (I) or a pharmacologically acceptable salt thereof as a means to solve the problem. [R1: a C1-C6 alkyl group or the like, R2: a C1-C6 alkyl group or the like, A: a 5-membered aromatic hetero-ring or the like, R3, R3′: a C1-C6 alkyl group or the like]

TECHNICAL FIELD

The present invention relates mainly to a compound having a specificchemical structure having a central anti-inflammatory effect or apharmacologically acceptable salt thereof, and to a pharmaceutical usethereof. In addition, the present invention relates to the mechanism ofaction, pharmaceutical composition, production of the pharmaceuticalcomposition, methods for prevention and/or treatment, and the like ofthe compound or the pharmacologically acceptable salt thereof.

BACKGROUND ART

Griseofulvin is an antibiotic that was first isolated from Penicilliumgriseofulvum, a species of penicillium mold of Aspergillus by AE Oxfordet al. in 1939 (non-patent literature 1). It is mainly orallyadministered, but it is a poorly soluble and easily absorbed drug, andthe oral absorption kinetics thereof are complicated. It is used as anantifungal agent against dermatophytes such as Microsporum(Microsporum), Trichophyton (Trichophyton), and Epidermophyton(Epidermophyton) (non-patent literature 2 and 3).

Griseofulvin binds to tubulin in cells. This arrests the cell cycle atthe G2/M phase, causes mitotic abnormalities, and suppresses the growthof various cells such as fungi, plants, and mammals. Growth suppressionin fungal cells is induced at very low concentrations compared tomammalian cells, presumably due to the higher binding affinity forfungal tubulin compared to mammalian tubulin. In addition, it also hasthe effect of suppressing dynamic instability of microtubules andstabilizing microtubule movement by binding to microtubule-associatedproteins (MAPs) (non-patent literature 4).

Griseofulvin has a growth suppression effect on human cancer cells andapoptosis-inducing activity and exhibits antitumor activity on tumorstransplanted into athymic nude mice when used in combination withnocodazole. Therefore, it is also expected to have an effect as ananticancer agent (non-patent literature 5).

On the other hand, it has been known for long time to have ananti-inflammatory effect in addition to an anti-fungal effect.

For example, it has been found to exhibit an anti-inflammatory effect onformalin edema and cotton pellet granuloma, which are rat inflammationmodels (non-patent literature 6). In actual clinical practice, it hasbeen reported that it exhibits a pharmacological effect on lichen planus(lichen planus) (non-patent literature 7), plasma cell cheilitis (plasmacell cheilitis) (non-patent literature 8), and pigmented purpuricdermatosis (pigmented purpuric dermatosis) (non-patent literature 9),which are non-fungal inflammatory skin diseases.

In addition, it has been reported that it exhibits pharmacologicaleffects on livedoid vasculitis (livedoid vasculitis) (non-patentliterature 9), polyarthritis such as shoulder-hand syndrome(shoulder-hand syndrome) and scapulo-humeral peryarthritis(scapulo-humeral peryarthritis) (non-patent literature 6 and 10).

It has been found to have an effect on microtubules of leukocytes and anantagonistic effect on histamine, serotonin, prostaglandin, and thelike, which are chemical mediators of inflammation in vitro (non-patentliterature 6), but the details of the mechanism of action ofgriseofulvin in the anti-inflammatory effect are not clear.

As described above, griseofulvin having various physiological activitieshas undergone conversion of various substituents, and derivatives havebeen synthesized to date (non-patent literature 11).

In recent years, with the progress of research, the relationship betweenmental disorders, neurodegenerative diseases, and inflammation has beenreported (non-patent literature 12 and 13).

It has been reported that stress increases the production ofinflammatory cytokines from microglia and that blood cytokine (TNFα andthe like) levels are high in patients with psychiatric disorders(depression, schizophrenia, and the like), and involvement of braininflammation in mental illness has been suggested. In addition, inneurodegenerative diseases typified by Alzheimer's disease, it has alsobeen suggested that proteins that are thought to be the cause thereofmay trigger brain inflammation by activation of microglia.

PRIOR ART LITERATURE Non-Patent Literature

-   Non-patent literature 1: Oxford A E, Raistrick H, Simonart P.    Studies in the biochemistry of micro-organisms: Griseofulvin,    C(17)H(17)O(6)Cl, a metabolic product of Penicilliun grisso-fulvum    Dierckx. 1537917094409_0. 1939 February; 33(2): 240-248.-   Non-patent literature 2: Gentles J C. Experimental ringworm in    guinea pigs: oral treatment with griseofulvin. Nature. 1958 Aug. 16;    182 (4633): 476-477.-   Non-patent literature 3: Williams D I, Marten R H, Sarkany I. Oral    treatment of ringworm with griseofulvin. Lancet. 1958 Dec. 6; 2    (7958): 1212-1213.-   Non-patent literature 4: Wehland J, Herzog W, Weber K, Interaction    of griseofulvin with microtubules, microtubule protein and tubulin.    J Mol Biol. 1977 Apr. 15; 111(3): 329-342.-   Non-patent literature 5: Ho Y S, Dubh J S, Jeng J H, Wang Y J, Liang    Y C, Lin C H, Tseng C J, Yu C F, Chen R J, Lin J K. Griseofulvin    potentiates antitumorigenesis effects of nocodazole through    induction of apoptosis and G2/M call cycle arrest in human    colorectal cancer cells. Int J Cancer. 2001 Feb. 1; 91(3): 393-401.-   Non-patent literature 6: Sorrentino L, Capasso F, Di Rosa M.    Anti-inflammatory properties of griseofulvin. Agents Actions. 1977    March; 7(1): 157-162.-   Non-patent literature 7: Sehgal V N, Bikhchandani R, Koranne R V,    Nayar M, Saxena H M. Histopathological evaluation of griseofulvin    therapy in lichen planus. A double-blind controlled study.    Dermatologica. 1980; 161(1): 22-27.-   Non-patent literature 8: Taaki K, Osada A, Tsukamoto K, Ohtake N,    Furue M. Treatment of plasma cell cheilitis with griseofulvin. J Am    Acad Dermatol. 1994 May; 30(5 Pt 1); 789-790.-   Non-patent literature 9: Tamaki K, Yasaka N, Osada A, Shibagaki N,    Furue M. Successful treatment of pigmented purpuric dermatosis with    griseofulvin. Br J Dermatol. 1995 January; 132(1): 159-160.-   Non-patent literature 10: Cohen A, Goldman J, Daniels R, Kanenson W.    Treatment of shoulder-hand syndrome with griseofulvin. J Am Med    Assoc. 1960 Jun. 4; 173: 542-543,-   Non-patent literature 11: Petersen A B, Ronnest M H, Larsen, T O,    Clausen M H. The Chemistry of Griseofulvin. Chem. Rev. 2814    December; 114: 12688-12107.-   Non-patent literature 12: Kadota A. Neuroinflammation Hypothesis of    Psychiatric Disorders, Psychiatria et Neurologia Japonica (2012)    Vol. 114, No. 2, 124-133-   Non-patent literature 13: Kadota A. Neurodegenerative Diseases,    Neuroinflammation and Microglia, Clinical Neurology (2014) 54,    1119-1121

SUMMARY OF THE INVENTION Problem to be Solved by the Invention

The present invention provides a compound having a specific chemicalstructure having a central anti-inflammatory effect useful as an activeingredient for the prevention and treatment of inflammatory diseases, apharmacologically acceptable salt thereof, a pharmaceutical use thereofand the like, or a novel production method thereof and an intermediatethereof. The compound of the present invention, or the pharmaceuticallyacceptable salt thereof, has various different properties from theanti-inflammatory agents existing to date, so it is considered to beuseful as a novel pharmaceutical.

In particular, the present invention provides a use for prevention andtreatment of central inflammatory diseases with griseofulvin based onthe finding of the central anti-inflammatory effect of griseofulvin.Furthermore, in the present invention, by optimizing the structure ofgriseofulvin, a compound having a superior central anti-inflammatoryeffect has been found, and a use thereof for prevention and treatment ofcentral inflammatory diseases is provided.

Means for Solving the Problem

The present inventors have conducted intensive studies for the purposeof developing a compound useful as an active ingredient for theprevention and treatment of central inflammatory disease, apharmacologically acceptable salt thereof, and the like; as a result,the compound, the pharmacologically acceptable salt thereof, thepharmaceutical use thereof, and the like of the present invention werefound. In addition, it has been found that the compound and thepharmacologically acceptable salt thereof of the present invention haveexcellent properties in terms of central anti-inflammatory activity,bioavailability, in vitro activity, in vivo activity, rapid effects ofthe drug, sustained drug effect, physical stability, drug interaction,toxicity, and the like, and are useful as pharmaceuticals.

That is, the present invention is as described below.

[1]

A compound of the general formula (1) or a pharmacologically acceptablesalt thereof.

[The symbols in the formula are defined as follows.

R¹:

A C1-C6 alkyl group optionally substituted with the same or differentone to two substituents selected from a substituent group X,a C3-C6 cycloalkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,ora 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group X

R²:

A C1-C6 alkyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C3-C6 cycloalkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,ora 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group X

A:

A 5-membered aromatic heterocyclic ring,a 6-membered aromatic heterocyclic ring,an 8-10 membered condensed aromatic heterocyclic ring,a 5-7 membered unsaturated heterocyclic ring,a 4-7 membered saturated heterocyclic ring,a benzene ring, —CH═, or a cyano group (when A is a cyano group, R³ andR^(3′) do not exist.)R³, R^(3′):R³ and R^(3′) are each independently a hydrogen atom, a halogen atom, acyano group, a hydroxy group, an oxo group,a C1-C6 alkyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C1-C6 alkoxy group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C2-C6 alkenyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C2-C6 alkynyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C3-C6 cycloalkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,an amino group optionally substituted with the same or different one totwo substituents selected from the substituent group X,a C1-C6 alkoxycarbonyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,a carbamoyl group optionally substituted with the same or different oneto two substituents selected from the substituent group X,a phenyl group optionally substituted with the same or different one totwo substituents selected from the substituent group X,a 5-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup X,a 6-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup X,a 5-7 membered unsaturated heterocyclic group optionally substitutedwith the same or different one to two substituents selected from thesubstituent group X,a 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group X,an 8-10 membered condensed aromatic heterocyclic group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group X, orR³ and R^(3′) may form a 5-7 membered unsaturated heterocyclic ring, a4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring asa ring that binds to each other and condenses with A, and the ring isoptionally substituted with the same or different one to twosubstituents selected from the substituent group X.Substituent group X:A halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkylgroup, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6halocycloalkyl group,a phenyl group optionally substituted with the same or different one totwo substituents selected from a substituent group Y,a 5-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup Y,a 6-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup Y,a 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y,a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxygroup, a C3-C6 halocycloalkoxy group,a phenoxy group optionally substituted with the same or different one totwo substituents selected from the substituent group Y,a 5-membered aromatic heterocyclic oxy group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y,a 6-membered aromatic heterocyclic oxy group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y,a 4-7 membered saturated heterocyclic oxy group optionally substitutedwith the same or different one to two substituents selected from thesubstituent group Y,a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, acarboxy group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonylgroup,a phenylcarbonyl group optionally substituted with the same or differentone to two substituents selected from the substituent group Y,a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, adi (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylaminogroup, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6alkylcarbonylamino group,a phenylcarbonylamino group optionally substituted with the same ordifferent one to two substituents selected from the substituent group Y,a 5-membered aromatic heterocyclic carbonylamino group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group Y,a 6-membered aromatic heterocyclic carbonylamino group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group Y, ora C1-C6 alkylsulfonylamino groupSubstituent group Y:A C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxygroup

However, as the compound of the general formula (1) or thepharmaceutically acceptable salt thereof, a compound or apharmaceutically acceptable salt thereof of the following generalformula (Z) is excluded.

It should be noted that the symbols in the formula for the compound of ageneral formula (Z) are defined as follows.

R¹:

A C1-C6 alkyl group or a hydroxy C1-C6 alkyl group

R²:

A C1-C6 alkyl group

A:

A 5-membered aromatic heterocyclic ring

R³:

A C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, or a C1-C6 alkoxyC1-C6 alkyl group]

[2]

The compound or the pharmacologically acceptable salt thereof accordingto [1], wherein the 5-membered aromatic heterocyclic ring or the5-membered aromatic heterocyclic group in A, R³, or R³ is any oneselected from the group shown below.

[3]

The compound or the pharmacologically acceptable salt thereof accordingto [1] or [2], wherein the 6-membered aromatic heterocyclic ring or the6-membered aromatic heterocyclic group in A, R³, or R^(3′) is any oneselected from the group shown below.

[4]

The compound or the pharmacologically acceptable salt thereof accordingto any one of [1] to [3], wherein the 8-10 membered condensed aromaticheterocyclic ring or the 8-10 membered condensed aromatic heterocyclicgroup in A, R³, or R^(3′) is any one selected from the group shownbelow.

[5]

The compound or the pharmacologically acceptable salt thereof accordingto any one of [1] to [4] wherein the 5-7 membered unsaturatedheterocyclic ring or 5-7 membered unsaturated heterocyclic group in A,R³, or R^(3′) is any one selected from the group shown below.

[6]

The compound or the pharmacologically acceptable salt thereof accordingto any one of [1] to [5] wherein the 4-7 membered saturated heterocyclicring or the 4-7 membered saturated heterocyclic group in A, R¹, R², orR³ is any one selected from the group shown below.

[7]

The compound or the pharmacologically acceptable salt thereof accordingto [1], wherein the compound of the general formula (1) is any compoundselected from the following group.

-   (2S,5′R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-6-[5-[(1    S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-4-ethoxy-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-4-(difluoromethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′    R)-7-chloro-3′,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(I H-pyrazol-5-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-6-[1-(2-methoxyethyl)    pyrazol-3-yl]-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-6-(1,8-dioxa-2-azaspiro    [4.5]dec-2-en-3-yl)-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro    [4.5]dec-2-en-3-yl) spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(3-pyridyl) spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[8]

A pharmaceutical composition containing the compound or thepharmacologically acceptable salt thereof as an active ingredientaccording to any one of [1] to [7].

[9]

The pharmaceutical composition according to [8], which is for theprevention and/or treatment of a central inflammatory disease.

[10]

A pharmaceutical composition for the prevention and/or treatment of acentral inflammatory disease, the pharmaceutical composition containinga compound of a general formula (1′) or a pharmacologically acceptablesalt thereof.

The symbols in the formula are defined as follows.

R¹:

A C1-C6 alkyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C3-C6 cycloalkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,ora 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group X

R²:

A C1-C6 alkyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C3-C6 cycloalkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,ora 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group X.

A:

A 5-membered aromatic heterocyclic ring,a 6-membered aromatic heterocyclic ring,an 8-10 membered condensed aromatic heterocyclic ring,a 5-7 membered unsaturated heterocyclic ring,a 4-7 membered saturated heterocyclic ring,a benzene ring, or a single bond (when it is a single bond, one or theother of R³ and R^(3′) is not present.)R³, R^(3′):R³ and R^(3′) are each independently a hydrogen atom, a halogen atom, acyano group, a hydroxy group,a C1-C6 alkyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C1-C6 alkoxy group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C2-C6 alkenyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C2-C6 alkynyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C3-C6 cycloalkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,an amino group optionally substituted with the same or different one totwo substituents selected from the substituent group X,a C1-C6 alkoxycarbonyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,a carbamoyl group optionally substituted with the same or different oneto two substituents selected from the substituent group X,a phenyl group optionally substituted with the same or different one totwo substituents selected from the substituent group X,a 5-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup X,a 6-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup X,a 5-7 membered unsaturated heterocyclic group optionally substitutedwith the same or different one to two substituents selected from thesubstituent group X,a 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group X,an 8-10 membered condensed aromatic heterocyclic group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group X,orR³ and R^(3′) may form a 5-7 membered unsaturated heterocyclic ring, a4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring asa ring that binds to each other and condenses with A, and the ring isoptionally substituted with the same or different one to twosubstituents selected from the substituent group X.Substituent group X:A halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkylgroup, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6halocycloalkyl group,a phenyl group optionally substituted with the same or different one totwo substituents selected from the substituent group Y,a 5-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup Y,a 6-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup Y,a 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y,a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxygroup, a C3-C6 halocycloalkoxy group,a phenoxy group optionally substituted with the same or different one totwo substituents selected from the substituent group Y,a 5-membered aromatic heterocyclic oxy group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y,a 6-membered aromatic heterocyclic oxy group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y,a 4-7 membered saturated heterocyclic oxy group optionally substitutedwith the same or different one to two substituents selected from thesubstituent group Y,a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, acarboxy group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonylgroup,a phenylcarbonyl group optionally substituted with the same or differentone to two substituents selected from the substituent group Y,a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, adi (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylaminogroup, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6alkylcarbonylamino group,a phenylcarbonylamino group optionally substituted with the same ordifferent one to two substituents selected from the substituent group Y,a 5-membered aromatic heterocyclic carbonylamino group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group Y,a 6-membered aromatic heterocyclic carbonylamino group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group Y, ora C1-C6 alkylsulfonylamino groupSubstituent group Y:A C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxygroup]

[11]

The pharmaceutical composition according to [10], wherein R¹ is a methylgroup, an ethyl group, or a hydroxyethyl group.

[12]

The pharmaceutical composition according to [10] or [11], wherein R² isa methyl group.

[13]

The pharmaceutical composition according to any one of [10] to [12],wherein the 5-membered aromatic heterocyclic ring or the 5-memberedaromatic heterocyclic group in A, R³, or R^(3′) is any one selected fromthe group shown below.

[14]

The pharmaceutical composition any one of [10] to [13], wherein the6-membered aromatic heterocyclic ring or the 6-membered aromaticheterocyclic group in A, R³, or R^(3′) is any one selected from thegroup shown below.

[15]

The pharmaceutical composition according to any one of [10] to [14],wherein the 5-7 membered unsaturated heterocyclic ring or the 5-7membered unsaturated heterocyclic group in A, R³, or R^(3′) is any oneselected from the group shown below.

[16]

The pharmaceutical composition according to any one of [10] to [15],wherein the 4-7 membered saturated heterocyclic ring or the 4-7 memberedsaturated heterocyclic group in A, R¹, R², or R³ is any one selectedfrom the group shown below.

[17]

The pharmaceutical composition according to any one of [10] to [12],wherein A is a 5-membered aromatic heterocyclic ring, R³ is a methylgroup, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3alkyl group, and R^(3′) is a hydrogen atom.

[18]

The pharmaceutical composition according to any one of [10] to [12],wherein A is any ring selected from the following group, and in the caseof two binding groups, R^(3′) is not present.

[* indicates a binding group.]

[19]

A pharmaceutical composition for the prevention and/or treatment of acentral inflammatory disease, the pharmaceutical composition containinga compound of a general formula (1″) or a pharmacologically acceptablesalt thereof.

[The symbols in the formula are defined as follows.

R¹: A methyl group or an ethyl groupR²: A methyl groupA: Any ring selected from the following group

[* indicates a binding group.]

R³: A methyl group or an ethyl group]

[20]

The pharmaceutical composition according to [10], wherein the compoundof the general formula (1′) is any compound selected from the followinggroup.

-   (2S,5′R)-7-chloro-6-(2-hydroxyethoxy)-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-6-(2-methoxyethoxy)-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(1-methylpyrazol-3-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl)-1,2,4-oxadiazol-3-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-6-[5-[(1    S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-6-[5-[(I    R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3′-methoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-4-ethoxy-6-[5-[(1    S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3′-methoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-6-[5-[(1    S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-4-ethoxy-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-4-(difluoromethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(1H-pyrazol-5-yl) spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-6-[1-(2-methoxyethyl)    pyrazol-3-yl]-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-6-(1,8-dioxa-2-azaspiro    [4.5]dec-2-en-3-yl)-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro    [4.5]dec-2-en-3-yl) spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(3-pyridyl) spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione-   (2S,5′R)-7-chloro-3′,4,6-trimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[21]

A pharmaceutical composition for the prevention and/or treatment of acentral inflammatory disease, the pharmaceutical composition containinga compound described below or a pharmacologically acceptable saltthereof.

-   (2S,5′R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[22]

A pharmaceutical composition for the prevention and/or treatment of acentral inflammatory disease, the pharmaceutical composition containinga compound described below or a pharmacologically acceptable saltthereof.

-   (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[23]

A pharmaceutical composition for the prevention and/or treatment of acentral inflammatory disease, the pharmaceutical composition containinga compound described below or a pharmacologically acceptable saltthereof.

-   (2S,5′R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[24]

A pharmaceutical composition for the prevention and/or treatment of acentral inflammatory disease, the pharmaceutical composition containinga compound described below or a pharmacologically acceptable saltthereof.

-   (2S,5′R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5′-methyl-spiro    [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[25]

A pharmaceutical composition for the prevention and/or treatment of acentral inflammatory disease, the pharmaceutical composition containinga compound described below or a pharmacologically acceptable saltthereof.

-   (2S,5′R)-7-chloro-4-ethoxy-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)    spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[26]

The pharmaceutical composition according to any one of [9] to [25],wherein the central inflammatory disease is any one selected from agroup consisting of

Alzheimer's disease, Parkinson's disease, Lewy body dementia, multiplesystem atrophy, Pick's disease, progressive supranuclear palsy, cerebralcortex basement degeneration, frontotemporal lobe degeneration,Huntington's disease, amyotrophic lateral sclerosis, spinal and bulbarmuscular atrophy, spinal muscular atrophy, spinocerebellar degeneration,multiple sclerosis, Creutzfeldt-Jakob disease, fatal familial insomnia,Gerstmann-Straussler-Scheinker syndrome, Down syndrome, Niemann-Pickdisease, cerebral amyloid angiopathy, HIV encephalopathy, influenzaencephalopathy, hepatic encephalopathy, progressive multifocalleukoencephalopathy, anti-NMDA receptor antibody encephalitis,cerebrovascular disorders, traumatic brain injuries, spinal cordinjuries, hypoxic encephalopathy, epilepsy, optic neuritis, congenitalmetabolic brain diseases, Wernicke's encephalopathy, autism spectrumdisorders, attention deficit/hyperactivity disorders, tic disorders,schizophrenia, bipolar disorders, major depressive disorders (treatmentresistant depression and postpartum depression), persistent depressivedisorders (dysthymic disorder), premenstrual dysthymic disorders,anxiety disorders, focal phobia, panic disorders, obsessive compulsivedisorders, emotional trauma and stress related disorders, eatingdisorders, circadian rhythm sleep/wake disorders, narcolepsy, substancerelated disorders (alcohol addiction and drug addiction), impulsecontrol disorders, delirium, personality disorders, and Rett's syndrome.

[27]

The pharmaceutical composition according to any one of [9] to [25],wherein the central inflammatory disease is any one selected from agroup consisting of

Alzheimer's disease, Parkinson's disease, Lewy body dementia, multiplesystem atrophy, Pick's disease, progressive supranuclear palsy, cerebralcortex basement degeneration, frontotemporal lobe degeneration,Huntington's disease, amyotrophic lateral sclerosis, spinal and bulbarmuscular atrophy, spinal muscular atrophy, spinocerebellar degeneration,multiple sclerosis, Creutzfeldt-Jakob disease, schizophrenia, bipolardisorders, major depressive disorders (treatment resistant depressionand postpartum depression), persistent depressive disorders (dysthymicdisorder), premenstrual dysthymic disorders, anxiety disorders, focalphobia, panic disorders, obsessive compulsive disorders, emotionaltrauma and stress related disorders, eating disorders, circadian rhythmsleep/wake disorders, narcolepsy, substance related disorders (alcoholaddiction and drug addiction), impulse control disorders, delirium,personality disorders, and Rett's syndrome

[28]

The pharmaceutical composition according to any one of [9] to [25],wherein the central inflammatory disease is any one selected from agroup consisting of

schizophrenia, bipolar disorders, major depressive disorders (treatmentresistant depression and postpartum depression), persistent depressivedisorders (dysthymic disorder), premenstrual dysthymic disorders,anxiety disorders, focal phobia, panic disorders, and obsessivecompulsive disorders.

[29]

A crystal of(2S,5′R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (example 4) having peaks atabout 9.5, 10.7, 14.1, 16.4, 17.9, 23.3, 23.6, 23.9, 24.4, and 27.2 asdiffraction angles (2θ (°)) in powder X-ray diffraction.

[30]

A crystal of(2S,5′R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (example 4) having the X-raydiffraction pattern shown in FIG. 1.

[31]

A crystal of(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (example 5) havingpeaks at about 10.0, 12.3, 15.6, 18.3, 19.1, 20.7, 22.3, 22.9, 24.2, and29.3 as diffraction angles (2θ (°)) in powder X-ray diffraction.

[32]

A crystal of(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (example 5) having theX-ray diffraction pattern shown in FIG. 2.

[33]

A crystal of(2S,5′R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (example 17) having peaks atabout 6.4, 11.2, 11.6, 12.7, 14.7, 17.0, 19.6, 22.4, 24.1, and 26.0 asdiffraction angles (2θ (°)) in powder X-ray diffraction.

[34]

A crystal of(2S,5′R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (example 17) having theX-ray diffraction pattern shown in FIG. 3.

[35]

A crystal of(2S,5′R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (example 25) having peaks atabout 8.1, 11.5, 13.2, 13.5, 14.0, 14.4, 20.8, 21.4, 22.3, and 25.3 asdiffraction angles (2θ (°)) in powder X-ray diffraction.

[36]

A crystal of(2S,5′R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (example 25) having theX-ray diffraction pattern shown in FIG. 4.

Effect of the Invention

The compound having a specific chemical structure having a centralanti-inflammatory effect or a pharmacologically acceptable salt thereofof the present invention has various properties different fromanti-inflammatory agents existing to date, so it is considered to beuseful as a novel pharmaceutical.

In addition, the compound and the pharmacologically acceptable saltthereof of the present invention have excellent properties in terms ofanti-inflammatory activity, bioavailability, in vitro activity, in vivoactivity, rapid effects of the drug, sustained drug effect, physicalstability, drug interaction, toxicity, and the like, and are useful aspharmaceuticals.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a powder X-ray diffraction pattern of the compound ofexample 4. The ordinate represents intensity (cps) and the abscissarepresents a diffraction angle (2θ (°)).

FIG. 2 shows a powder X-ray diffraction pattern of the compound ofexample 5. The ordinate represents intensity (cps) and the abscissarepresents a diffraction angle (2θ (°)).

FIG. 3 shows a powder X-ray diffraction pattern of the compound ofexample 17. The ordinate represents intensity (cps) and the abscissarepresents a diffraction angle (2θ (°)).

FIG. 4 shows a powder X-ray diffraction pattern of the compound ofexample 25. The ordinate represents intensity (cps) and the abscissarepresents a diffraction angle (2θ (°)).

EMBODIMENTS

The present invention will be described in detail below.

Substituents, Explanation of Terms, and the Like

An aspect of the present invention includes the compound of the generalformula (1) or the pharmacologically acceptable salt thereof.

[The symbols in the formula are defined as follows.

R¹:

A C1-C6 alkyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C3-C6 cycloalkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,ora 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group X

R²:

A C1-C6 alkyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C3-C6 cycloalkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,ora 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group X

A:

A 5-membered aromatic heterocyclic ring,a 6-membered aromatic heterocyclic ring,an 8-10 membered condensed aromatic heterocyclic ring,a 5-7 membered unsaturated heterocyclic ring,a 4-7 membered saturated heterocyclic ring,a benzene ring, —CH═, or a cyano group (when A is a cyano group, R³ andR^(3′) do not exist)R³, R^(3′):R³ and R^(3′) are each independently a hydrogen atom, a halogen atom, acyano group, a hydroxy group, an oxo group,a C1-C6 alkyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C1-C6 alkoxy group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C2-C6 alkenyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C2-C6 alkynyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C3-C6 cycloalkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,an amino group optionally substituted with the same or different one totwo substituents selected from the substituent group X,a C1-C6 alkoxycarbonyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,a carbamoyl group optionally substituted with the same or different oneto two substituents selected from the substituent group X,a phenyl group optionally substituted with the same or different one totwo substituents selected from the substituent group X,a 5-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup X,a 6-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup X,a 5-7 membered unsaturated heterocyclic group optionally substitutedwith the same or different one to two substituents selected from thesubstituent group X,a 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group X,an 8-10 membered condensed aromatic heterocyclic group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group X, orR³ and R^(3′) may form a 5-7 membered unsaturated heterocyclic ring, a4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring asa ring that binds to each other and condenses with A, and the ring isoptionally substituted with the same or different one to twosubstituents selected from the substituent group X. It should be notedthat the ring formed by R³ and R^(3′) binding to each other andcondensing with A includes a spiro ring.Substituent group X:A halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkylgroup, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6halocycloalkyl group,a phenyl group optionally substituted with the same or different one totwo substituents selected from the substituent group Y,a 5-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup Y,a 6-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup Y,a 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y,a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxygroup, a C3-C6 halocycloalkoxy group,a phenoxy group optionally substituted with the same or different one totwo substituents selected from the substituent group Y,a 5-membered aromatic heterocyclic oxy group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y,a 6-membered aromatic heterocyclic oxy group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y,a 4-7 membered saturated heterocyclic oxy group optionally substitutedwith the same or different one to two substituents selected from thesubstituent group Y,a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, acarboxy group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonylgroup,a phenylcarbonyl group optionally substituted with the same or differentone to two substituents selected from the substituent group Y,a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, adi (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylaminogroup, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6alkylcarbonylamino group,a phenylcarbonylamino group optionally substituted with the same ordifferent one to two substituents selected from the substituent group Y,a 5-membered aromatic heterocyclic carbonylamino group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group Y,a 6-membered aromatic heterocyclic carbonylamino group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group Y, ora C1-C6 alkylsulfonylamino groupSubstituent group Y:A C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxygroupHowever, as the compound of the general formula (1) or thepharmaceutically acceptable salt thereof, a compound or apharmaceutically acceptable salt thereof of the following generalformula (Z) is excluded.

It should be noted that the symbols in the formula for the compound ofthe general formula (Z) are defined as follows.

R¹:

A C1-C6 alkyl group or a hydroxy C1-C6 alkyl group

R²:

A C1-C6 alkyl group

A:

A 5-membered aromatic heterocyclic ring

R³:

A C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, or a C1-C6 alkoxyC1-C6 alkyl group]

In addition, an aspect of the present invention includes thepharmaceutical composition for the prevention and/or treatment of acentral inflammatory disease, which contains the compound of the generalformula (1′) or the pharmacologically acceptable salt thereof.

[The symbols in the formula are defined as follows.

R¹:

A C1-C6 alkyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C3-C6 cycloalkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,ora 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group X.

R²:

A C1-C6 alkyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C3-C6 cycloalkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,ora 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group X.

A:

A 5-membered aromatic heterocyclic ring,a 6-membered aromatic heterocyclic ring,an 8-10 membered condensed aromatic heterocyclic ring,a 5-7 membered unsaturated heterocyclic ring,a 4-7 membered saturated heterocyclic ring,a benzene ring, or a single bond (when it is a single bond, one or theother of R³ and R^(3′) is not present.)R³, R^(3′):R³ and R^(3′) are each independently a hydrogen atom, a halogen atom, acyano group, a hydroxy group,a C1-C6 alkyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C1-C6 alkoxy group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C2-C6 alkenyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C2-C6 alkynyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X,a C3-C6 cycloalkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,an amino group optionally substituted with the same or different one totwo substituents selected from the substituent group X,a C1-C6 alkoxycarbonyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,a carbamoyl group optionally substituted with the same or different oneto two substituents selected from the substituent group X,a phenyl group optionally substituted with the same or different one totwo substituents selected from the substituent group X,a 5-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup X,a 6-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup X,a 5-7 membered unsaturated heterocyclic group optionally substitutedwith the same or different one to two substituents selected from thesubstituent group X,a 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group X,an 8-10 membered condensed aromatic heterocyclic group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group X, orR³ and R^(3′) may form a 5-7 membered unsaturated heterocyclic ring, a4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring asa ring that binds to each other and condenses with A, and the ring isoptionally substituted with the same or different one to twosubstituents selected from the substituent group X. It should be notedthat the ring formed by R³ and R^(3′) binding to each other andcondensing with A includes a spiro ring.Substituent group X:A halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkylgroup, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6halocycloalkyl group,a phenyl group optionally substituted with the same or different one totwo substituents selected from the substituent group Y,a 5-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup Y,a 6-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup Y,a 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y,a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxygroup, a C3-C6 halocycloalkoxy group,a phenoxy group optionally substituted with the same or different one totwo substituents selected from the substituent group Y,a 5-membered aromatic heterocyclic oxy group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y,a 6-membered aromatic heterocyclic oxy group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y,a 4-7 membered saturated heterocyclic oxy group optionally substitutedwith the same or different one to two substituents selected from thesubstituent group Y,a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, acarboxy group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonylgroup,a phenylcarbonyl group optionally substituted with the same or differentone to two substituents selected from the substituent group Y,a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, adi (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylaminogroup, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6alkylcarbonylamino group,a phenylcarbonylamino group optionally substituted with the same ordifferent one to two substituents selected from the substituent group Y,a 5-membered aromatic heterocyclic carbonylamino group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group Y,a 6-membered aromatic heterocyclic carbonylamino group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group Y, ora C1-C6 alkylsulfonylamino groupSubstituent group Y:A C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxygroup]

A further aspect of the present invention includes a substituent of thecompound of the general formula (1′) in the pharmaceutical compositionfor prevention and/or treatment of a central inflammatory disease, thepharmaceutical composition containing the compound of the generalformula (1′) or the pharmacologically acceptable salt thereof and is acase described below.

The 5-membered aromatic heterocyclic ring for A is the same as describedabove, but more preferably, it represents the following 5-membered ring.(It should be noted that in this case, R^(3′) is not present.)

[* indicates a binding group.]

The 5-membered aromatic heterocyclic ring forms the following compoundas the compound of the general formula (1′) depending on the bindinggroup.

in the formula, R¹, R², and R³ have the same meaning as in the case ofthe compound of the above general formula (1′).]

In the present specification, the “5-membered aromatic heterocyclicring” is a monocyclic 5-membered aromatic heterocyclic ring containingone to four atoms selected from the group consisting of a nitrogen atom,an oxygen atom, and a sulfur atom. For example, rings such as thoseshown below are included.

In the present specification, the “6-membered aromatic heterocyclicring” is a monocyclic 6-membered aromatic heterocyclic ring containingone to four atoms selected from the group consisting of a nitrogen atom,an oxygen atom, and a sulfur atom. For example, rings such as thoseshown below are included.

In the present specification, the “8-10 membered aromatic heterocyclicring” is a monocyclic 8-10 membered condensed aromatic heterocyclic ringcontaining one to four atoms selected from the group consisting of anitrogen atom, an oxygen atom, and a sulfur atom. For example, ringssuch as those shown below are included.

In the present specification, the “5-7 membered unsaturated heterocyclicring” is a ring in which a monocyclic 5-7 membered saturatedheterocyclic ring is partially oxidized or a ring in which an aromaticheterocyclic ring is partially reduced containing one to four atomsselected from the group consisting of a nitrogen atom, an oxygen atom,and a sulfur atom. For example, rings such as those shown below areincluded.

In the present specification, the “4-7 membered saturated heterocyclicring” is a monocyclic 4-7 membered saturated heterocyclic ringcontaining one to four atoms selected from the group consisting of anitrogen atom, an oxygen atom, and a sulfur atom. For example, ringssuch as those shown below are included as monocyclic 4-7 memberedsaturated heterocyclic rings.

The “halogen atom” in the present specification is a fluorine atom, achlorine atom, a bromine atom, or an iodine atom, and it is preferably afluorine atom or a chlorine atom.

The “C1-C6 alkyl group” in the present specification is a linear orbranched alkyl group having one to six carbon atoms. Examples thereofinclude a methyl group, an ethyl group, a 1-propyl group, an isopropylgroup, a 1-butyl group, a 2-butyl group, a 2-methyl-1-propyl group, a2-methyl-2-propyl group, a 1-pentyl group, a 2-pentyl group, a 3-pentylgroup, a 2-methyl-2-butyl group, a 3-methyl-2-butyl group, a 1-hexylgroup, a 2-hexyl group, a 3-hexyl group, a 2-methyl-1-pentyl group, a3-methyl-1-pentyl group, a 2-ethyl-1-butyl group, a 2,2-dimethyl-1-butylgroup, and a 2,3-dimethyl-1-butyl group, and it is preferably a methylgroup or an ethyl group.

The “C2-C6 alkenyl group” in the present specification is a linear orbranched alkenyl group having two to six carbon atoms, and it may haveone or two or more carbon-carbon double bonds. For example, it is avinyl group, a 2-propenyl (allyl) group, a 2-butenyl group, a 2-pentenylgroup, a 3-methyl-2-butenyl group, a 2-hexenyl group, or a3-methyl-2-pentenyl group, and preferably, it is a vinyl group or anallyl group.

The “C2-C6 alkynyl group” in the present specification is a linear orbranched alkynyl group having two to six carbon atoms, and it may haveone or two or more carbon-carbon triple bonds. For example, it is anethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynylgroup, a 2-butynyl group, a 1-pentynyl group, a 2-pentynyl group, or1-hexynyl group, and it is preferably an ethynyl group or a 1-propynylgroup.

The “C1-C6 alkoxy group” in the present specification is a group inwhich an oxygen atom is bonded to a C1-C6 alkyl group. Examples thereofinclude a methoxy group, an ethoxy group, a 1-propoxy group, a 2-propoxygroup, a 1-butoxy group, a 2-butoxy group, a 2-methyl-1-propoxy group, a2-methyl-2-propoxy group, a 1-pentyloxy group, a 2-pentyloxy group, a3-pentyloxy group, a 2-methyl-2-butoxy group, a 3-methyl-2-butoxy group,a 1-hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a2-methyl-1-pentyloxy group, and a 3-methyl-1-pentyloxy group.Preferably, it is a methoxy group, an ethoxy group, a 1-propoxy group,or a 2-propoxy group.

The “C3-C6 cycloalkyl group” in the present specification is a cyclicalkyl group having three to six carbon atoms, and it is preferably acyclopropyl group, a cyclobutyl group, a cyclopentyl group, or acyclohexyl group.

The “hydroxy C1-C6 alkyl group” in the present specification is a groupin which a hydroxyl group is bonded to a C1-C6 alkyl group. For example,it is a hydroxymethyl group or a hydroxyethyl group.

The “C1-C6 alkoxy C1-C6 alkyl group” in the present specification is agroup in which a C1-C6 alkoxy is bonded to a C1-C6 alkyl group. Examplesthereof include a methoxymethyl group, a methoxyethyl group, anethoxymethyl group, and an ethoxyethyl group.

The “C1-C6 haloalkyl group” in the present specification is a group inwhich a halogen atom is bonded to a C1-C6 alkyl group. Examples thereofinclude a fluoromethyl group, a difluoromethyl group, a dichloromethylgroup, a dibromomethyl group, a trifluoromethyl group, a trichloromethylgroup, a 2-fluoroethyl group, a 2-bromoethyl group, a 2-chloroethylgroup, a 2-iodoethyl group, a 2,2-difluoroethyl group, a2,2,2-trifluoroethyl group, a trichloroethyl group, a pentafluoroethylgroup, a 3-fluoropropyl group, a 3-chloropropyl group, and a4-fluorobutyl group. It is preferably a trifluoromethyl group.

The “C3-C6 halocycloalkyl group” in the present specification is a groupin which a halogen atom is bonded to a C3-C6 cycloalkyl group, andexamples thereof include a fluorocyclopropyl group, a fluorocyclobutylgroup, a fluorocyclopentyl group, and a fluorocyclohexyl group.

The “C1-C6 haloalkoxy group” in the present specification is a group inwhich a halogen atom is bonded to a C1-C6 alkoxy group, and examplesthereof include a fluoromethoxy group, a difluoromethoxy group, adichloromethoxy group, a dibromomethoxy group, a trifluoromethoxy group,a trichloromethoxy group, a 2-fluoroethoxy group, a 2-bromoethoxy group,a 2-chloroethoxy group, a 2-iodoethoxy group, a 2,2-difluoroethoxygroup, a 2,2,2-trifluoroethoxy group, a trichloroethoxy group, apentafluoroethoxy group, a 3-fluoropropoxy group, a 3-chloropropoxygroup, and a 4-fluorobutoxy group. It is preferably a trifluoromethoxygroup.

The “C3-C6 cycloalkoxy group” in the present specification is a group inwhich a C3-C6 cycloalkyl group is bonded to an oxygen atom, and it ispreferably a cyclopropyloxy group, a cyclobutyloxy group, acyclopentyloxy group, or a cyclohexyloxy group.

The “C3-C6 halocycloalkoxy group” in the present specification is agroup in which a C3-C6 halocycloalkyl group is bonded to an oxygen atom,and examples thereof include a fluorocyclopropoxy group, afluorocyclobutoxy group, a fluorocyclopentyloxy group, and afluorocyclohexyloxy group.

The “5-membered aromatic heterocyclic oxy group” in the presentspecification is a group in which a 5-membered aromatic heterocyclicring is bonded to an oxygen atom.

The “6-membered aromatic heterocyclic oxy group” in the presentspecification is a group in which a 6-membered aromatic heterocyclicring is bonded to an oxygen atom.

The “4-7 membered saturated heterocyclic oxy group” in the presentspecification is a group in which a 4-7 membered saturated heterocyclicring is bonded to an oxygen atom.

The “C1-C6 alkoxycarbonyl group” in the present specification is a groupin which a C1-C6 alkoxy group is bonded to a carbonyl group, andexamples thereof include a methoxycarbonyl group, an ethoxycarbonylgroup, and a propoxycarbonyl group.

The “C3-C6 cycloalkoxycarbonyl group” in the present specification is agroup in which a C3-C6 cycloalkoxy group is bonded to a carbonyl group,and it is preferably a cyclopropyloxycarbonyl group, acyclobutyloxycarbonyl group, a cyclopentyloxycarbonyl group, or acyclohexyloxycarbonyl group.

The “C1-C6 alkyl carbonyl group” in the present specification is a groupin which a C1-C6 alkyl group is bonded to a carbonyl group, and examplesthereof include a methyl carbonyl group, an ethyl carbonyl group, or apropyl carbonyl group.

The “mono (C1-C6 alkyl) aminocarbonyl group” in the presentspecification is a group in which one C1-C6 alkyl group is bonded to theamino group of an aminocarbonyl group, and it is preferably amethylaminocarbonyl group, an ethylaminocarbonyl group, or apropylaminocarbonyl group.

The “di (C1-C6 alkyl) aminocarbonyl group” in the present specificationis a group in which two C1-C6 alkyl groups are bonded to the amino groupof an aminocarbonyl group, and it is preferably a dimethylaminocarbonylgroup, a diethylaminocarbonyl group, or a dipropylaminocarbonyl group.

The “mono (C1-C6 alkyl) aminosulfonyl group” in the presentspecification is a group in which one C1-C6 alkyl group is bonded to theamino group of an aminosulfonyl group, and it is preferably amethylaminosulfonyl group, an ethylaminosulfonyl group, or apropylaminosulfonyl group.

The “di (C1-C6 alkyl) aminosulfonyl group” in the present specificationis a group in which two C1-C6 alkyl groups are bonded to the amino groupof the aminosulfonyl group, and it is preferably a dimethylaminosulfonylgroup, a diethylaminosulfonyl group, or a dipropylaminosulfonyl group.

The “mono (C1-C6 alkyl) amino group” in the present specification is agroup in which one C1-C6 alkyl group is bonded to an amino group, and itis preferably a methylamino group, an ethylamino group, or a propylaminogroup.

The “di (C1-C6 alkyl) amino group” in the present specification is agroup in which two C1-C6 alkyl groups are bonded to an amino group, andit is preferably a dimethylamino group, a diethylamino group, or adipropyl amino group.

The “C1-C6 alkoxycarbonylamino group” in the present specification is agroup in which a C1-C6 alkoxycarbonyl group is bonded to an amino group,and for example, it is a methoxycarbonylamino group, anethoxycarbonylamino group, or a propoxycarbonylamino group.

The “mono (C1-C6 alkyl) aminocarbonylamino group” in the presentspecification is a group in which a mono (C1-C6 alkyl) aminocarbonylgroup is bonded to an amino group, and it is preferably amethylaminocarbonylamino group, an ethylaminocarbonylamino group, or apropylaminocarbonylamino group.

The “di (C1-C6 alkyl) aminocarbonylamino group” in the presentspecification is a group in which a di (C1-C6 alkyl) aminocarbonyl groupis bonded to an amino group, and it is preferably adimethylaminocarbonylamino group, a diethylaminocarbonylamino group, ora dipropylaminocarbonylamino group.

The “5-membered aromatic heterocyclic carbonylamino group” in thepresent specification is a group in which a 5-membered aromaticheterocyclic carbonyl group is bonded to an amino group.

The “6-membered aromatic heterocyclic carbonylamino group” in thepresent specification is a group in which a 6-membered aromaticheterocyclic carbonyl group is bonded to an amino group.

The “C1-C6 alkylsulfonylamino group” in the present specification is agroup in which a C1-C6 alkyl group is bonded to the sulfonyl group of asulfonylamino group, and it is preferably a methylsulfonylamino group,an ethylsulfonylamino group, or a propylsulfonylamino group.

The “pharmacologically acceptable salt” indicates a salt that can beused as a pharmaceutical. When the compound has an acidic group or abasic group, since it can be converted to a basic salt or an acidic saltby reacting with a base or an acid, it indicates a salt thereof.

The pharmacologically acceptable “basic salt” of the compound preferablyincludes an alkali metal salt such as a sodium salt, a potassium salt,and a lithium salt; an alkaline earth metal salt such as a magnesiumsalt and a calcium salt; organic base salts such as an N-methylmorpholine salt, a triethylamine salt, a tributylamine salt, adiisopropylethylamine salt, a dicyclohexylamine salt, anN-methylpiperidine salt, a pyridine salt, a 4-pyrrolidinopyridine salt,and a picoline salt; and an amino acid salt such as glycine salt, alysine salt, an arginine salt, an ornithine salt, a glutamate, and anaspartate, and it is preferably an alkali metal salt.

The pharmacologically acceptable “acidic salt” of the compoundpreferably includes an inorganic acid salt such as a hydrohalide such asa hydrofluoride, a hydrochloride, a hydrobromide, and a hydroiodide, anitrate, a perchlorate, a sulfate, and a phosphate; an organic salt suchas a lower alkanesulfonate such as methanesulfonate,trifluoromethanesulfonate, and ethanesulfonate, an aryl sulfonate suchas a benzenesulfonates, and a p-toluene sulfonate, an acetate, a malate,a fumarate, a succinate, a citrate, an ascorbate, a tartrate, anoxalate, a maleate, and the like; and an amino acid salt such as glycinesalt, a lysine salt, an arginine salt, an ornithine salt, a glutamate,and an aspartate, and it is most preferably a hydrohalide (inparticular, a hydrochloride).

The compound of the present invention or the pharmacologicallyacceptable salt thereof may absorb moisture, adhere to adsorbed water,or become hydrate by leaving in the air or recrystallization. Thepresent invention also encompasses compounds of such various hydrates,solvates, and crystalline polymorphs.

The compounds of the present invention, their pharmacologicallyacceptable salts or solvates thereof, depending on the type andcombination of substituents, may have various isomers such as geometricisomers such as a cis isomer and a trans isomer, tautomers, or opticalisomers such as a d isomer and an l isomer, while the compounds includethose all isomers, stereoisomers, and mixtures of these isomers andstereoisomers in any ratio unless otherwise specified. Mixtures of theseisomers may be resolved by known resolution means.

The compounds of the present invention also include labels, that is, acompound in which one or more atoms of the compounds are substitutedwith an isotope (for example, 2H, 3H, 13C, 14C, 35S, and the like).

In addition, the present invention also encompasses so-called a prodrug.The prodrug is a compound having a group which can converted to an aminogroup, a hydroxyl group, a carboxyl group, or the like of the compoundby hydrolysis or under physiological conditions, and as a group formingsuch a prodrug, it is a group described in Prog. Med., Vol. 5, pp. 2157to 2161 (1985) or the like. As the prodrug, more specifically,

when an amino group is present in the compound,a compound in which the amino group is acylated, alkylated, orphosphorylated (for example, it is a compound in which the amino groupis eicosanoylated, alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated,tetrahydrofuranylated, pyrrolidinyl methylated, pivaloyloxymethylatied,or tert-butylated, or the like) and the like are included, andwhen a hydroxyl group is present in the compound,a compound in which the hydroxyl group is acylated, alkylated,phosphorylated, or borated (for example, it is a compound in which thehydroxyl group is acetylated, palmitoylated, propanoylated,pivaloylated, succinylated, fumarylated, alanylated, ordimethylaminomethyl carbonylated, or the like.) and the like areincluded.In addition, when a carboxy group is present in the compound,a compound in which the carboxy group is esterified or amidated (forexample, it is a compound in which the carboxy group is ethylesterified, phenyl esterified, carboxymethyl esterified,dimethylaminomethyl esterified, pivaloyloxymethyl esterified,ethoxycarbonyloxyethyl esterified, amidated, or methylamidated, or thelike.), and the like are included.

In the present specification, unless otherwise described, the values ofthe powder X-ray diffraction analysis are values obtained using Cu-Kαradiation. When an X-ray other than Cu-Kα radiation is used, 2θ (°)varies according to the equation 2d sin θ=nλ (d is the distance betweentwo surfaces, n is an arbitrary integer, λ is the wavelength of theX-ray), but these are merely expressions of the crystals of the presentinvention by substantially equivalent alternative expression methods andare included in the scope of the present invention, which can be easilyunderstood by those skilled in the crystal arts. In addition, therelative intensities of the peaks shown by these charts may varydepending on, for example, the degree of crystallization of the sample,the method of preparation, or the like. 2θ (°) does not varysubstantially, but it can vary within an error range (generally a rangeof ±0.2°) recognized by those skilled in the crystal arts. In thecharacteristic peak of powder X-ray diffraction represented by the angle2θ, “about” indicates ±0.2°, and in another embodiment, it indicates±0.1°.

Due to the nature of the data, the value of the powder X-ray diffractionanalysis should not be interpreted strictly sine what is important isthe crystal lattice spacing and the overall pattern in determining theidentity of crystals, and since the relative intensity can varydepending somewhat on the direction of crystal growth, particle size,and measurement conditions.

(Production Method)

A Production method is described below. However, the method forproducing the compound or the salt thereof is not limited to thefollowing method in any way.

[Method A]

A method A is a method for producing a compound (A-III) of the presentinvention.

[In the formula, R¹, R², and R³ have the same meaning as in the case ofthe compound of the above general formula (1) or (1′). X indicates aleaving group such as a halogen group.]

(A1 Step) Demethylation Step

This is a step of obtaining a compound (A-II) from a compound (A-I)using a metal halide in the presence of a base and a crown ether.

Examples of the base include triethylamine, diisopropylethylamine,pyridine, and the like.

Examples of the crown ether include 18-crown-6 and the like.

Examples of the metal halide include potassium iodide and the like.

The solvent may include, for example, N,N-dimethylformamide or the like,or a non-solvent, the reaction temperature is usually about 60 to 120°C., and the reaction time is usually about 1 to 24 hours.

(A2 Step) Alkylation Step

(When Using Halogenated Alkyl)

This is a step of obtaining the compound (A-III) from the compound(A-II) using a corresponding alkylation reagent in the presence of abase.

Examples of the alkylation reagent include a halogenated alkyl such asan alkyl iodide and an alkyl bromide, a sulfonate ester such as alkyltosylate and alkyl mesylate, diethyl (bromodifluoromethyl) phosphonate,sodium chlorodifluoro acetate, and the like.

Examples of the base include triethylamine, diisopropylethylamine,potassium carbonate, potassium hydroxide, and the like.

As the solvent, tetrahydrofuran, 1,4-dioxane, acetonitrile,dichloromethane, N,N-dimethylformamide, and the like, are included, anda mixture thereof is included. The reaction temperature is usually about0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.

(In the Case of Using the Mitsunobu Reaction)

This is a step of obtaining the compound (A-III) from the compound(A-II) using a corresponding alcohol in the presence of a phosphine andan azodicarboxylic acid ester or a diazodicarboxamide.

Examples of the phosphine include triphenyl phosphine, tri-n-butylphosphine, and the like are included.

Examples of the azodicarboxylate or diazodicarboxamide include diethylazodicarboxylate, di-tert-butyl azodicarboxylate, 1,1′-(azodicarbonyl)dipyridine, and the like.

As the solvent, tetrahydrofuran, 1,4-dioxane, toluene, and the like, areincluded, and a mixture thereof is included. The reaction temperature isusually about 0 to 100° C., and the reaction time is usually about 0.5to 24 hours.

[Method B]

A method B is a method for producing a compound (B-III) (a compoundcorresponding to the compound (A-I) used in the method A). When R¹ is amethyl group, the compound (B-III) may be produced without carrying outthese steps.

[In the formula, R¹ and R² have the same meaning as in the case of thecompound of the above general formula (1) or (1′), and X has the samemeaning as described above.]

(B1 Step) Demethylation Step

This is a step of obtaining a compound (B-II) from a compound (B-I)using a metal halide.

Examples of the metal halide include magnesium iodide and the like.

Examples of the solvent include toluene, tetrahydrofuran, 1,4-dioxane,and the like, or a mixture thereof may be included.

The reaction temperature is usually about 60 to 120° C., and thereaction time is usually about 0.5 to 24 hours.

(B2 Step) Alkylation Step

This is a step of obtaining the compound (B-Ill) from the compound(B-II). It may be carried out by the method similar to (A2 step).

[Method C]

A Method C is a method for producing a compound (C-III) of the presentinvention from a compound (C-I) (a compound corresponding to thecompound (A-II) used in the method A).

[In the formula, R¹, R², R³, and A have the same meaning as in the caseof the compound of the above general formula (1) or (1′). Tf indicates atrifluoromethane sulfonyl group, B* indicates a boronic acid or aboronic acid pinacol ester or the like.]

(C1 Step) Trifluoromethane Sulfonylation Step

This is a step of obtaining a compound (C-II) from the compound (C-I) inthe presence of a base using a trifluoromethane sulfonylation reagent.

Examples of the trifluoromethane sulfonylation reagent include atrifluoromethane sulfonic acid anhydride, a trifluoromethane sulfonicacid chloride, N-phenylbis (trifluoromethane sulfone imide), and thelike.

Examples of the base include triethylamine, diisopropylethylamine, andthe like.

The solvent may include, for example, terhydrofuran, 1,4-dioxane,acetonitrile, dichloromethane, and the like, and it may include amixture thereof.

The reaction temperature is usually about −20° C. to room temperature,and the reaction time is usually about 0.5 to 24 hours.

(C2 Step) Step of Carrying Out Coupling Reaction Using Transition MetalCatalyst

This is a step of obtaining the compound (C-III) using a palladiumcatalyst and a boronic acid or a boronic acid pinacol ester of R³-A inthe presence of a base from the compound (C-II).

Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenyl phosphino) ferrocene] dichloropalladium, tris (dibenzylidene acetone) dipalladium, palladium acetate,acetyl acetone palladium, bis (triphenyl phosphine) palladiumdichloride, and the like.

Examples of the base include triethylamine, diisopropylethylamine,1,8-diazabicyclo [5.4.0]-7-undecene (DBU), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), potassium hydrogen carbonate, sodiumbicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide,sodium hydroxide, potassium phosphate, sodium phosphate, and the like.

Examples of the solvent, methanol, ethanol, tetrahydrofuran,1,4-dioxane, water, N,N-dimethylformamide, dimethylsulfoxide, toluene,and the like may be included. A mixture thereof may be included.

The reaction temperature is usually about 60 to 120° C., and thereaction time is usually about 0.5 to 12 hours.

[Method D]

A method D is a method for producing a compound (D-IV) of the presentinvention from a compound (D-I) (a compound corresponding to thecompound (C-II) used in the method C).

[In the formula, R¹, R², and R³ have the same meaning as in the case ofthe compound of the above general formula (1) or (1′). Tf indicates thesame meaning as described above, and R⁴ indicates a phenyl groupoptionally has a substituent.]

(D1 Step) Step of Coupling with Formate Ester

This is a step of obtaining a compound (D-II) from the compound (D-I)using a formate ester in the presence of a base and a palladium catalyst(a phosphine ligand).

Examples of the base include triethylamine, diisopropylethylamine,dimethylaminopyridine, potassium carbonate, sodium carbonate, potassiumhydroxide, sodium hydroxide, and the like.

Examples of the formate ester include phenyl formate, formate(2,4,6-trichlorophenyl), and the like.

Examples of the palladium catalyst include palladium acetate, palladiumacetylacetonate, palladium trifluoroacetate, palladium dichloride, tris(dibenzylidene acetone) dipalladium, bis (triphenyl phosphine) palladiumdichloride, and the like.

Examples of the phosphine ligand to be used simultaneously with thepalladium catalyst may include 4,5-bis (diphenyl phosphino)-9,9-dimethylxanthene (xantphos), 1,1′-bis (diphenyl phosphino) ferrocene (dppf),2,2′-bis (diphenyl phosphino)-1,1-binaphthyl (BINAP), bis (diphenylphosphino) methane (DPPM), triphenyl phosphine, 1,2-bis (diphenylphosphino) ethane (DPPE), and the like.

Examples of the solvent include N,N-dimethylformamide, toluene,tetrahydrofuran, acetonitrile, and the like, and a mixture thereof isincluded.

The reaction temperature is usually about room temperature to 120° C.,and the reaction time is usually about one to eight hours.

(D2 Step) Step of Carrying Out Amidation with Acylhydrazine

This is a step of obtaining a compound (D-III) from the compound (D-II)using a corresponding acylhydrazine in the presence of a base.

Examples of the base include triethylamine, diisopropylethylamine,dimethylaminopyridine, potassium carbonate, sodium carbonate, potassiumhydroxide, sodium hydroxide, and the like. As an additive,N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt),1-hydroxy-7-azabenzotriazole (HOAt), or the like may be advantageous infacilitating the reaction.

Examples of the solvent include N,N-dimethylformamide, dichloromethane,tetrahydrofuran, acetonitrile, and the like, and a mixture thereof isincluded.

The reaction temperature is usually about 0 to 60° C., and the reactiontime is usually about 1 to 12 hours.

(D3 Step) Ring Formation Step

This is a step of obtaining the compound (D-IV) from the compound(D-III) using a dehydrating agent.

Examples of the dehydrating agent include a (methoxycarbonyl sulfamoyl)triethylammonium hydroxide inner salt, phosphoryl chloride,polyphosphoric acid, sulfuric acid, triphenyl phosphine/iodine, succinicacid, tosylate, tosyl chloride, and the like.

Examples of the solvent include toluene, acetonitrile, dichloromethane,and the like, and a mixed solvent thereof and non-solvent are included.

The reaction temperature is usually about 0 to 100° C., and the reactiontime is usually about 0.5 to 24 hours.

[Method E]

A method E is a method for producing a compound (E-III) of the presentinvention from the compound (E-I) (a compound corresponding to acompound (D-II) used in the method D).

[In the formula, R¹, R², and R³ have the same meaning as in the case ofthe compound of the above general formula (1) or (1′), and R⁴ has thesame meaning as described above.]

(E1 Step) Step of Carrying Out Acylation with Amidoxime

This is a step of obtaining a compound (E-II) from a compound (E-I)using a corresponding amidoxime in the presence of a base.

Examples of the base include triethylamine, diisopropylethylamine,dimethylaminopyridine, potassium carbonate, sodium carbonate, potassiumhydroxide, sodium hydroxide, and the like, and as an additive,N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt),1-hydroxy-7-azabenzotriazole (HOA), or the like may be advantageous infacilitating the reaction.

Examples of the solvent include N,N-dimethylformamide, dichloromethane,tetrahydrofuran, acetonitrile, and the like, and a mixture thereof isincluded.

The reaction temperature is usually about room temperature to 80° C.,and the reaction time is usually about 1 to 12 hours.

(E2 Step) Ring Formation Step

This is a step of obtaining a compound (E-III) by stirring the compound(E-II) in a solvent at room temperature or under heating.

Examples of the solvent include toluene, N,N-dimethylformamide,dichloromethane, tetrahydrofuran, acetonitrile, and the like, and amixture thereof is included.

The reaction temperature is usually about room temperature to 100° C.,and the reaction time is usually about 0.5 to 24 hours.

[Method F]

A method F is a method for producing a compound (F-V) of the presentinvention from a compound (F-I) (a compound corresponding to thecompound (C-II) used in the method C).

[In the formula, R¹, R², and R³ have the same meaning as in the case ofthe compound of the above general formula (1) or (1′), and Tf has thesame meaning as described above.]

(F1 Step) Step of Carrying Out Cyanation Using Transition Metal Catalyst

This is a step of obtaining a compound (F-II) from a compound (F-I) inthe presence or absence of a phosphine and in the presence of zinccyanide and a palladium catalyst.

Examples of the palladium catalyst include tris (dibenzylidene acetone)dipalladium, bis [tri (tert-butyl) phosphine] palladium, tetrakis(triphenyl phosphine) palladium, bis (trifluoro acetoxy) palladium, andthe like.

Examples of the phosphine include triphenyl phosphine, tri (tert-butyl)phosphine, tri-o-toluyl phosphine, diphenyl phosphinoferrocene, diphenylphosphinobutane, and the like. Examples of the solvent includeN-methyl-2-pyrrolidone, N,N-dimethylformamide, and the like, and amixture thereof is included.

The reaction temperature is usually about 80 to 120° C., and thereaction temperature is usually about one to eight hours.

(F2 Step) Hydroxylamine Addition Step

This is a step of obtaining a compound (F-III) from the compound (F-II)using hydroxylamine.

Examples of the solvent include methanol, ethanol, dimethylsulfoxide,water, and the like, and a mixture of these solvents is included.

The reaction temperature is usually about room temperature to 100° C.,and the reaction time is usually about 0.5 to 24 hours.

(F3 Step) Step of Acylation of Oxime

This is a step of obtaining a compound (F-IV) from the compound (F-III)in the presence of a condensing agent and a base using a correspondingcarboxylic acid.

Examples of the condensing agent includesO-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine (DMT-MM),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC or EDCI), and thelike.

Examples of the base include triethylamine, diisopropylethylamine,dimethylaminopyridine and the like.

As an additive, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole(HOBt), l-hydroxy-7-azabenzotriazole (HOAt), or the like may beadvantageous in facilitating the reaction.

Examples of the solvent may include ethanol, tetrahydrofuran,acetonitrile, N,N-dimethylformamide, dichloromethane, toluene, and thelike, and a mixture of these solvents may be included.

The reaction temperature is usually about room temperature to 60° C.,and the reaction time is usually about 0.5 to 24 hours.

(F4 Step) Ring Formation Step

This is a step of obtaining the compound (F-V) by stirring the compound(F-IV) in a solvent at room temperature or under heating.

Examples of the solvent may include toluene, N,N-dimethylformamide,dichloromethane, tetrahydrofuran, acetonitrile, and the like, and amixture thereof is included.

The reaction temperature is usually about 60 to 120° C., and thereaction time is usually about 0.5 to 24 hours.

[Method G]

A method G is a method for producing a compound (G-III) of the presentinvention from a compound (G-I).

[In the formula, R¹, R², and R³ have the same meaning as in the case ofthe compound of the above general formula (1) or (1′), and X has thesame meaning as described above.]

(G1 Step) Demethylation Step

This is a step of obtaining a compound (G-II) from the compound (G-I).It may be carried out by the method similar to (B1 step).

(G2 Step) Alkylation Step

This step is a step of obtaining a compound (G-III) from the compound(G-II). It may be carried out by the method similar to (A2 step).

[Method H]

A method H is a method for producing a compound (H-II) of the presentinvention by deprotecting the protective group when R¹ or R³ of thecompound (H-I) contains a protective group.

[In the formula, R¹, R², R³, and A have the same meaning as in the caseof the compound of the above general formula (1) or (1′), and R¹‘ andR’, indicate protected R¹ and R³, respectively.]

(H1 Step) Deprotection Step

(In the case of tetrahydropyranyl (THP)

This is a step of obtaining the compound (H-II) from the compound (H-I)containing a hydroxy group protected with a tetrahydropyranyl groupusing an acid.

Examples of the acid include hydrochloric acid, sulfuric acid,hydrochloric acid-methanol, hydrochloric acid-1,4-dioxane, hydrochloricacid-ethyl acetate, acetic acid, p-toluene sulfonic acid, or pyridiniump-toluene sulfonate.

Examples of the solvent include methanol, ethanol, tetrahydrofuran,water, a mixture thereof, and the like.

The reaction temperature is usually about 0 to 80° C., and the reactiontime is usually about 0.5 to 24 hours.

(In the Case of Silyl Group)

This is a step of obtaining the compound (H-II) from the compound (H-I)containing a hydroxy group protected by a silyl group using adesilylation reagent.

Examples of the desilylation reagent include an acid or tetrabutylammonium fluoride (TBAF), hydrogen fluoride, hydrogen fluoride pyridine,and the like.

Examples of the acid may include hydrochloric acid, sulfuric acid,hydrochloric acid-methanol, hydrochloric acid-1,4-dioxane, hydrochloricacid-ethyl acetate, acetic acid, p-toluene sulfonic acid,trifluoroacetic acid, and the like, and it is also possible to react ata catalyst amount.

Examples of the solvent may include methanol, ethanol, tetrahydrofuran,1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, water, and the like, anda mixture thereof may be included.

The reaction temperature is usually about 0 to 60° C., and the reactiontime is usually about 0.5 to 24 hours.

[Method I]

A method I is a method for producing a compound (I-IV) of the presentinvention from a compound (I-I) (a compound corresponding to thecompound (D-II) used in the method D).

[In the formula, R¹, R², and R³ have the same meaning as in the case ofthe compound of the above general formula (1) or (1′), and R⁴ has thesame meaning as described above.]

(I1 Step) Step of Carrying Out Amidation with Hydrazine

This is a step for obtaining a compound (I-II) from the compound (I-I)using hydrazine in the presence of a base.

Examples of the base include triethylamine, diisopropylethylamine,dimethylaminopyridine, potassium carbonate, sodium carbonate, potassiumhydroxide, sodium hydroxide, and the like. As an additive,N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt),1-hydroxy-7-azabenzotriazole (HOAt), or the like may be advantageous infacilitating the reaction.

Examples of the solvent may include N,N-dimethylformamide,dichloromethane, tetrahydrofuran, acetonitrile, and the like, and amixture thereof is included.

The reaction temperature is usually about 0 to 30° C., and the reactiontime is usually about 1 to 24 hours.

(I2 Step) Step of Acylating Acylhydrazine

This is a step of obtaining a compound (I-III) from the compound (I-II)in the presence of a condensing agent and a base using a correspondingcarboxylic acid.

Examples of the condensing agent includeO-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (DMT-MM),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC or EDCI), and thelike.

Examples of the base include triethylamine, diisopropylethylamine,dimethylaminopyridine, and the like.

As an additive, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole(HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), or the like may beadvantageous in facilitating the reaction.

Examples of the solvent may include ethanol, tetrahydrofuran,acetonitrile, N,N-dimethylformamide, dichloromethane, toluene, and thelike, and a mixture of these solvents may be included.

The reaction temperature is usually about room temperature to 60° C.,and the reaction time is usually about 0.5 to 24 hours.

(D3 Step) Ring Formation Step

This is a step of obtaining the compound (I-IV) from the compound(I-III). It may be carried out by the method similar to (D3 step).

[Method J]

A method J is a method for producing a compound (J-V) of the presentinvention from a compound (J-I) (a compound corresponding to thecompound (C-II) used in the method C).

[In the formula, R¹ and R² have the same meaning as in the case of thecompound of the above general formula (1) or (1′), and R⁵ and R⁶ eachindependently indicate hydrogen, a C1-C6 alkyl group, or a 5-7 memberedunsaturated heterocyclic ring, a 4-7 membered saturated heterocyclicring, or a C3-C6 cycloalkyl ring, in which both are bonded to eachother.]

(J1 Step) Step of Carrying Out Hydroxymethylation Using Transition MetalCatalyst

This is a step of obtaining a compound (J-II) from the compound (J-I)using tributylstannyl methanol in the presence or absence of a phosphineand in the presence of a palladium catalyst.

Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, bis (triphenyl phosphine) palladium (II)dichloride, and the like.

Examples of the phosphine include triphenyl phosphine, tri-o-toluylphosphine, and the like.

Examples of the solvent may include 1,4-dioxane, ethanol, orN,N-dimethylformamide, and the like, and a mixture thereof is included.

The reaction temperature is usually about 80 to 120° C., and thereaction time is usually about 1 to 24 hours.

(J2 step) Step of oxidation of alcohol

This is a step of obtaining a compound (J-III) by reacting the compound(J-II) with an oxidizing agent.

Examples of the oxidizing agent include Dess-Martin Periodinane(Dess-Martin Periodinane), dimethyl sulfoxide, chromic acid, and thelike.

Examples of the solvent include dichloromethane, acetonitrile, and thelike.

The reaction temperature is usually about −20° C. to 40° C., and thereaction time is usually about 0.5 to 24 hours.

(J3 Step) Oximation Step

This is a step of obtaining a compound (J-IV) from the compound (J-III)using hydroxylamine or a hydrochloride thereof in the presence orabsence of a base.

Examples of the base include sodium acetate, sodium hydroxide, sodiumbicarbonate, potassium carbonate, pyridine, and the like.

Examples of the solvent include methanol, ethanol, water, and the like,and a mixture thereof is included.

The reaction temperature is usually about room temperature to 100° C.,and the reaction time is usually about 1 to 24 hours.

(J4 Step) Ring Formation Step

This is a step of obtaining the compound (J-V) from the compound (J-IV)using a chlorination reagent in the presence or absence of a base.

Examples of the base include triethylamine, diisopropylethylamine,pyridine, 1,8-diazabicyclo [5.4.0]-7-undecene (DBU), and the like.

Examples of the chlorinating reagent include N-chlorosuccinimide (NCS),sodium hypochlorite, tert-butyl hypochlorite, and the like.

Examples of the solvent include N,N-dimethylformamide, dichloromethane,chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, water, and thelike, and a mixture thereof is included.

The reaction temperature is usually about −20 to 40° C., and thereaction time is usually about 1 to 24 hours.

[Method K]

A method K is a method for producing a compound (K-II) of the presentinvention by alkylating R^(1′) or R^(3′) of a compound (K-I).

[In the formula, R¹, R², R³, and A have the same meaning as in the caseof the compound of the above general formula (1) or (1′), and R^(1′) andR^(3′) each independently indicate a C1-C6 alkyl group which has asubstituent containing a hydrogen atom or active hydrogen such as, ahydroxyl group or an amino group.]

(K1 Step) Alkylation Step

(When Using Halogenated Alkyl)

This is a step of obtaining the compound (K-H) from the compound (K-I).It may be carried out by the method similar to (A2 step).

(When Using Reductive Amination Reaction)

This is a step of obtaining the compound (K-II) by reacting the compound(K-I) with a corresponding aldehyde in the presence or absence of anacid using a reducing agent.

Examples of the reducing agent include sodium triacetoxy borohydride,sodium cyanoborohydride, and the like.

Examples of the acid may include acetic acid, tetraisopropylorthotitanate, zinc chloride, and the like.

Examples of the solvent include methanol, acetonitrile, water,tetrahydrofuran, dichloromethane, and the like, and a mixture thereofmay be included. The reaction temperature is usually about 0 to 80° C.,and the reaction time is usually about 0.5 to 24 hours.

The compounds produced by the above methods may be isolated and purifiedby known methods such as extraction, precipitation, distillation,chromatography, fractional recrystallization, and recrystallization.

In addition, when the compound or intermediate of production hasasymmetric carbon, optical isomers exist. Each of may be isolated andpurified by a conventional method such as fractional recrystallization(salt resolution) in which these optical isomers are recrystallized byconversion to appropriate salts and column chromatography. As areference document for the method of resolving an optical isomer fromracemates, J. Jacques et al., “Enantiomers, Racemates and Resolution,John Wiley And Sons, Inc.” may be included.

(Administration Form)

Administration may be carried out by any form of oral administration bya tablet, a pill, a capsule, a granule, a powder, a solution, or thelike, or by any forma of parenteral administration by an injection forintra-articular, intravenous, intramuscular, or the like, a suppository,an eye drop, an eye ointment, a transdermal solution, an ointment, atransdermal patch, a transmucosal solution, a transmucosal patch, aninhalant, or the like.

As a solid composition for oral administration,

a tablet, a powder, a granule, and the like are used. Such a solidcomposition is composed of one or more active ingredients and at leastone inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone,magnesium metasilicate aluminate, and/or the like. The solid compositionmay contain, according to a conventional method, an inert additive suchas a lubricant such as magnesium stearate, a disintegrant such as sodiumcarboxymethyl starch, a stabilizer, and a solubilizer. The tablet orpill may be coated with a sugar coating or a film of a substance solublein the stomach or intestine, if necessary.

As a liquid composition for oral administration,

a pharmaceutically acceptable emulsion, solution, suspension, syrup,elixir, or the like is used. To such a liquid composition, it ispossible to add generally used inert diluent such as purified water orethanol. The liquid composition may contain, in addition to an inertdiluent, a solubilizer, an adjuvant such as a wetting agent, asweetening agent, a flavoring agent, a fragrance, and a preservative.

As an injection for parenteral administration,

a sterile aqueous or non-aqueous solution, a suspension or an emulsion,and the like are used. The aqueous solvent includes, for example,distilled water for injection, physiological saline, and the like. Thenon-aqueous solvents include, for example, propylene glycol,polyethylene glycol, and vegetable oil such as olive oil, alcohols suchas ethanol, Polysorbate 80, and the like. Such an injection compositionmay further contain a tonicity agent, a preservative, a wetting agent,an emulsion, a dispersing agent, a stabilizer, or a solubilizer. Theseinjection compositions can be sterilized by, for example, filtrationthrough a bacteria retention filter, application of a bactericide, orirradiation. In addition, these injection compositions may be used byproducing a sterile solid composition and dissolved or suspended insterile water or a sterile solvent for injection prior to use.

As an external preparation,

an ointment, a plaster, a cream, a jelly, a cataplasm, a spray, alotion, an eye drop, an eye ointment, and the like are used. Theseexternal preparations include generally used ointment bases, lotionbases, aqueous or non-aqueous solutions, suspensions, emulsions, and thelike. For example, as an ointment or lotion base, polyethylene glycol,propylene glycol, white petrolatum, bleached beeswax, polyoxyethylenehydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetylalcohol, lauromacrogol, sorbitan sesquioleate, and the like are used.

A transmucosal agent such as an inhalant and a transnasal agent are usedin solid, liquid, or semisolid form, and it may be produced according toa conventionally known method. For example, a known excipient, andfurthermore, a pH adjuster, a preservative, a surfactant, a lubricant, astabilizer, a thickener, and the like may be added as appropriate. Withthese transmucosal agents, devices appropriate for inhalation orinsufflation may be used as the method of administration. For example,the compound may be administered alone or as a powder of a formulatedmixture, or as a solution or suspension in combination with apharmaceutically acceptable carrier, using known devices and nebulizers,such as metered dose inhalation devices. A dry powder inhaler or thelike may be for single or multiple administration, and a dry powder orpowder containing capsule may be also used. Alternatively, anappropriate ejector may be used. For example, it may be in the form of apressurized aerosol spray or the like using a suitable gas such aschlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.

(Dosage)

In the case of normal oral administration, the appropriate daily dose isabout 0.001 to 100 mg/kg, preferably 0.1 to 30 mg/kg, and morepreferably 0.1 to 10 mg/kg of body weight. This is administered in onedose or separated into two or more doses. When administeredintravenously, the appropriate daily dose is about 0.0001 to 10 mg/kg ofbody weight, which is administered once or separated into several timesa day.

In addition, as a transmucosal agent, about 0.001 to 100 mg/kg of bodyweight is administered once or separated into several times a day. Thedose is appropriately determined depending on the individual case inconsideration of symptoms, age, sex, and the like.

(Combined Usage)

In the present invention, it may be used in combination with varioustherapeutic agents or preventive agents for diseases that are consideredto exhibit the efficacy thereof. The combination may be administeredsimultaneously, separately and continuously or at desired timeintervals. The co-administered formulations may be blended or formulatedseparately, even if it is a compounding agent.

(Formulation Example 1) Powder

A powder is obtained by mixing 5 g of the compound of the presentinvention or the salt thereof, 895 g of lactose, and 100 g of cornstarch in a blender.

(Formulation Example 2) Granule

After 5 g of the compound of the present invention or the salt thereof,865 g of lactose, and 100 g of low substituted hydroxypropyl celluloseare mixed, 300 g of a 10% hydroxypropyl cellulose aqueous solution isadded and kneaded. This is granulated using an extrusion granulator anddried to obtain granules.

(Formulation Example 3) Tablet

After 5 g of the compound of the present invention or the salt thereof,90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose, and1 g of magnesium stearate are mixed with a blender, and tablets areobtained by tableting with a tableting machine.

The pharmacological activity of the compound of the present invention orthe pharmacologically acceptable salt thereof was confirmed by thefollowing test.

(Test Example) Forced Swim Test

Male ddY mice (4 weeks old at the time of evaluation) were used for thetest in groups of 10 mice. The mice were placed in a water bath (innerdiameter 14.5 cm, height 20 cm, water temperature about 24° C.) withwater filled to a height of about 15 cm, and a swimming trial wascarried out for 15 minutes (training trial). The next day, mice wereorally administered with a suspension of each compound (10 mL/kg,solvent: 0.5% methylcellulose aqueous solution) was orally administeredto the mice, and four hours later, they were placed in the water bath.Immobility time (sec) was measured for six minutes immediately afterthat, and the ratio of the average immobility time of each compoundadministration group with respect to the average immobility time of acontrol group (10 mL/kg administration of 0.5% methylcellulose aqueoussolution without a compound) was calculated.

TABLE 1 Ratio of the average Example No. Dose (mg/kg) immobility time(%) Griseofulvin 100 72 2 10 71 3 10 84 4 10 61 5 10 62 6 10 67 17 10 7218 10 85 21 10 87 22 10 88 24 10 65 25 10 58 26 10 72 28 10 80 30 10 7031 10 68

The results of this test indicate a decrease in average immobility timefrom the comparison with the control group in each compoundadministration group used in the present test, and the effect of thecompound of the present invention could be confirmed from the presenttest.

According to the test results, it was indicated that the compound of thepresent invention or the pharmacologically acceptable salt thereof waseffective for the prevention and/or treatment of central inflammatorydiseases such as Alzheimer's disease, Parkinson's disease, Lewy bodydementia, multiple system atrophy, Pick's disease, progressivesupranuclear palsy, cerebral cortex basement degeneration,frontotemporal lobe degeneration, Huntington's disease, amyotrophiclateral sclerosis, spinal and bulbar muscular atrophy, spinal muscularatrophy, spinocerebellar degeneration, multiple sclerosis,Creutzfeldt-Jakob disease, fatal familial insomnia,Gerstmann-Straussler-Scheinker syndrome, Down syndrome, Niemann-Pickdisease, cerebral amyloid angiopathy, HIV encephalopathy, influenzaencephalopathy, hepatic encephalopathy, progressive multifocalleukoencephalopathy, anti-NMDA receptor antibody encephalitis,cerebrovascular disorders, traumatic brain injuries, spinal cordinjuries, hypoxic encephalopathy, epilepsy, optic neuritis, congenitalmetabolic brain diseases, Wernicke's encephalopathy, autism spectrumdisorders, attention deficit/hyperactivity disorders, tic disorders,schizophrenia, bipolar disorders, major depressive disorders (treatmentresistant depression and postpartum depression), persistent depressivedisorders (dysthymic disorder), premenstrual dysthymic disorders,anxiety disorders, focal phobia, panic disorders, obsessive compulsivedisorders, emotional trauma and stress related disorders, eatingdisorders, circadian rhythm sleep/wake disorders, narcolepsy, substancerelated disorders (alcohol addiction and drug addiction), impulsecontrol disorders, delirium, personality disorders, and Rett's syndrome.

EXAMPLE

Hereinafter, the present invention will be described in more detail byway of examples, but the scope of the present invention is not limitedthereto.

In the following examples, nuclear magnetic resonance (hereinafter, ¹HNMR) spectra were described using δ values (ppm) as chemical shiftvalues with tetramethylsilane as a standard substance. The split patternis indicated by s for singlet, d for doublet, t for triplet, q forquartet, m for multiplet, and br for broad.

Example 1(2S,5′R)-7-chloro-6-(2-hydroxyethoxy)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(1a)(2S,5′R)-7-chloro-6-hydroxy-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-6-hydroxy-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(+)-griseofulvin ((2S,5′R)-7-chloro-3′,4,6-trimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione, CAS number: 126-07-8,Product code: G0384 (Tokyo Chemical Industry)) (50 g), potassium iodide(23.5 g), and 18-crown 6-ether (41.2 g) were dissolved in pyridine (500mL), the mixture was stirred at 120° C. for nine hours and allowed tostand at room temperature overnight.

The reaction mixture was concentrated, 4%0 sodium bicarbonate aqueoussolution was added, and the mixture was washed twice with ethyl acetate.The aqueous layer was neutralized with 1 mol/L hydrochloric acid andextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: dichloromethane/ethanol=99/1 (V/V)] to obtain 19.4 g of a crudeproduct.

After ethyl acetate was added to solidify, and filtration was carriedout to obtain 15.2 g (yield: 32%) of the title compound as a whitesolid.

(1b)(2S,5′R)-7-chloro-6-(2-hydroxyethoxy)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-6-(2-hydroxyethoxy)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-6-hydroxy-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (0.1 g) of example 1 (1a)was dissolved in N,N-dimethylformamide (3 mL), 2-bromoethanol (0.0738 g)and potassium carbonate (0.102 g) were added and stirred at 100° C. forsix hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: ethyl acetate] to obtain 38 mg (yield: 34%) of the titlecompound as a pale yellow solid.

Example 2(2S,5′R)-7-chloro-3′,4-dimethoxy-6-(2-methoxyethoxy)-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-6-(2-methoxyethoxy)-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-6-hydroxy-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (30 mg) of example 1 (1a)was dissolved in N,N-dimethylformamide (1 mL), 2-bromoethylmethyl ether(136 mg) and potassium carbonate (135 mg) were added and stirred at 80°C. for six hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: ethyl acetate] to obtain 20 mg (yield: 57%) of the titlecompound as a white solid.

Example 3(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(1-methylpyrazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(3a)[(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate[(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate

(2S,5′R)-7-chloro-6-hydroxy-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (20 g) of example 1 (1a) wasdissolved in dichloromethane (300 mL), N-phenylbis(trifluoromethanesulfonimide) (25.3 g) and triethylamine (20.6 mL) wereadded, and the mixture was allowed to stand at room temperatureovernight.

The reaction mixture was diluted with dichloromethane, and the organiclayer was washed with water and saturated saline and dried withanhydrous sodium sulfate. The residue, which was obtained by distillingthe solvent under reduced pressure, was purified by silica gel columnchromatography [elution solvent: n-hexane/ethyl acetate=8/2 to 3/7(V/V)] to obtain 23.5 g (yield: 85%) of the title compound as a whitesolid.

(3b)(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(1-methylpyrazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(1-methylpyrazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate (76 mg) ofexample 3 (3a) was dissolved in N,N-dimethylformamide (1.6 mL), and1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.0403 g), potassium carbonate (0.0669 g), and [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct(0.0131 g) were added at room temperature and stirred at 80° C. forthree hours.

After the reaction temperature was returned to room temperature, thereaction mixture was diluted with ethyl acetate, and the insolublesubstances were filtered. The filtrate was poured into water andextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=1/1 to 0/1 (V/V)] to obtain 27 mg(yield: 42%) of the title compound as a white solid.

Example 4(2S,5′R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate (0.5 g) ofexample 3 (3a) was dissolved in toluene (10 mL), and1-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.283 g), chloro (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)] palladium (II) (0.167 g), and saturatedsodium bicarbonate aqueous solution (5 mL) were added and stirred at 90°C. for two hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=1/1 to 0/1 (V/V)] to obtain 266 mg(yield: 60%) of the title compound as a white solid.

Example 5(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(5a)(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate

[(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate (20 g) ofexample 3 (3a) was dissolved in toluene (200 mL), and palladium (II)acetate (0.477 g), 4,5-bis (diphenyl phosphino)-9,9-dimethylxanthene(2.46 g), and N,N-diisopropylethylamine (14.8 mL) were added and heatedto 80° C. 2,4,6-trichlorophenyl formate (12.5 g) was added in threeportions every 30 min.

After stirring at 80° C. for 30 min, the reaction mixture was pouredinto water, and the reaction mixture was extracted with ethyl acetate.The organic layer was washed with water and saturated saline and driedwith anhydrous sodium sulfate. The residue, which was obtained bydistilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: n-hexane/ethyl acetate=7/3to 3/7 (V/V)] to obtain 19.5 g (yield: 84%) of the title compound as awhite solid.

(5b)(2S,5′R)—N′-acetyl-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide(2S,5′R)—N′-acetyl-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide

(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (35 g) of example 5 (5a) wasdissolved in dichloromethane (400 mL): 3H-1,2,3-triazolo[4,5-b]pyridine-3-ol (8.72 g), acetohydrazide (purity: 90%, 7.12 g),4-dimethylaminopyridine (0.783 g), and triethylamine (26.8 mL) wereadded; and the mixture was allowed to stand at room temperatureovernight.

The reaction solution was washed with water and saturated saline anddried with anhydrous sodium sulfate. The residue, which was obtained bydistilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: methanol/ethyl acetate=0/10to 1/9 (V/V)] to obtain 23.4 g (yield: 86%) of the title compound as awhite solid.

(5c)(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)—N′-acetyl-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide (0.25 g) of example 5(5b) was dissolved in toluene (5 mL) and anhydrous 1,4-dioxane (5 mL), a(methoxycarbonyl sulfamoyl) triethylammonium hydroxide inner salt (0.169g) was added, and the mixture was stirred at 60° C. for one hour.

Water was added to the reaction mixture, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline and dried with anhydrous sodium sulfate. The residue,which was obtained by distilling the solvent under reduced pressure, waspurified by silica gel column chromatography [elution solvent:n-hexane/ethyl acetate=1/1 to 0/1 (V/V)] to obtain 49 mg (yield: 20%) ofthe title compound as a white solid.

Example 6(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(6a)[(Z)-1-aminoethylideneamino](2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate[(Z)-1-aminoethylideneamino](2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate

(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (3 g) of example 5 (5a) wasdissolved in dichloromethane (50 mL); N′-hydroxyethanimidamide (0.488g), 3H-1,2,3-triazolo [4,5-b]pyridine-3-ol (0.748 g),4-dimethylaminopyridine (0.0671 g), and triethylamine (2.28 mL) wereadded; and the mixture was allowed to stand at room temperatureovernight.

The reaction solution was diluted with ethyl acetate, and the organiclayer was washed with water and saturated saline and dried withanhydrous sodium sulfate. The residue, which was obtained by distillingthe solvent under reduced pressure, was purified by silica gel columnchromatography [elution solvent: n-hexane/ethyl acetate=80/20 to 0/100(V/V)] to obtain 2.32 g (yield: quantitative) of the title compound as awhite solid.

(6b)(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[(Z)-1-aminoethylideneamino](2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (0.95 g) of example 6 (6a)was dissolved in toluene (20 mL) and stirred at 110° C. for six hours.

The residue obtained by concentrating the reaction solution was purifiedby silica gel column chromatography [elution solvent: n-hexane/ethylacetate=8/2 to 3/7 (V/V)], and trituration was carried out with n-hexaneand ethyl acetate to obtain 756 mg (yield: 83%) of the title compound asa white solid.

Example 7(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(7a)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbonitrile(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbonitrile

[(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate (1 g) ofexample 3 (3a) was dissolved in N,N-dimethylformamide (10 mL), tetrakis(triphenyl phosphine) palladium (0) (0.245 g) and zinc cyanide (0.499 g)were added, and the mixture was stirred at 90° C. for five hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=8/2 to 3/7 (V/V)] to obtain 540 mg(yield: 73%) of the title compound as a pale yellow solid.

(7b)(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbonitrile (0.54 g) of example 7 (7a)was dissolved in ethanol (10 mL), 50% hydroxylamine aqueous solution(0.19 mL) was added, and the mixture was stirred at 90° C. for sixhours.

The reaction solution was concentrated and azeotroped twice withtoluene. The residue was dissolved in dichloromethane (20 mL); aceticacid (0.0891 mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride (0.299 g), 3H-1,2,3-triazolo [4,5-b]pyridine-3-ol (0.0424g), and triethylamine (0.652 mL) were added; and the mixture was stirredat room temperature for five hours.

The reaction solution was diluted with dichloromethane, and the organiclayer was washed with water and saturated saline and dried withanhydrous sodium sulfate. The residue, which was obtained by distillingthe solvent under reduced pressure was roughly purified by silica gelcolumn chromatography [elution solvent: n-hexane/ethyl acetate=1/1 to0/1 (V/V)]. The obtained crude product was suspended in toluene (5 mL)and stirred at 100° C. for seven hours.

Water was added to the reaction mixture, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=7/3 to 2/8 (V/V)] to obtain 34 mg(yield: 5.4%, three steps) of the title compound as a white solid.

Example 8(2S,5′R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(8a)(2S,5′R)-7-chloro-N′-(2-hydroxy-2-methyl-propanoyl)-1′,4-dimethoxy-5′-methyl-33′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide(2S,5′R)-7-chloro-N′-(2-hydroxy-2-methyl-propanoyl)-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide

(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-l′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (0.5 g) of example 5 (5a)was dissolved in dichloromethane (10 mL);2-hydroxy-2-methylpropanohydrazide (0.162 g), 3H-1,2,3-triazolo[4,5-b]pyridine-3-ol (0.125 g), 4-dimethylaminopyridine (0.0224 g), andtriethylamine (0.639 mL) were added; and the mixture was allowed tostand at room temperature overnight.

The residue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: methanol/ethyl acetate=0/10 to 1/9 (V/V)] to obtain 415 mg(yield: 97%) of the title compound as a white solid.

(8b)(2S,5′R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-N′-(2-hydroxy-2-methyl-propanoyl)-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide (0.415 g) of example 8(8a) was dissolved in dichloromethane (5 mL), triethylamine (0.62 mL)and p-toluene sulfonyl chloride (0.254 g) were added, and the mixturewas stirred at room temperature for two hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: methanol/ethyl acetate=0/10 to 1/9 (V/V)] to obtain 141 mg(yield: 35%) of the title compound as a white solid.

Example 9 (2S,5′R)-7-chloro-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1l′,3-dione

(9a)(2S)-2-tetrahydropyran-2-yloxypropanehydrazide(2S)-2-tetrahydropyran-2-yloxypropanehydrazide

Methyl (2S)-2-tetrahydropyran-2-yloxypropanoate (CAS Registry Number:153829-63-1, J. Org. Chem. 1991, 56, 1088-1093.) (2.2 g) was dissolvedin ethanol (8 mL), hydrazine monohydrate (1.8 g) was added, and themixture was allowed to stand overnight at room temperature. The residue,which was obtained by distilling the solvent under reduced pressure, waspurified by silica gel column chromatography [elution solvent:methanol/ethyl acetate=0/10 to 1/9 (V/V)] to obtain 1.6 g (yield: 73%)of the title compound as a white solid.

(9b)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-N′-[(2S)-2-tetrahydropyran-2-yloxypropanoyl]spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-N′-[(2S)-2-tetrahydropyran-2-yloxypropanoyl]spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide

(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (0.5 g) of example 5 (5a)was dissolved in dichloromethane (10 mL);(2S)-2-tetrahydropyran-2-yloxypropanehydrazide (0.258 g) of example 9(9a), 3H-1,2,3-triazolo [4,5-b]pyridine-3-ol (0.125 g),4-dimethylaminopyridine (0.0112 g), and N,N-diisopropylethylamine (0.478mL) were added; and the mixture was allowed to stand at room temperatureovernight.

The reaction mixture was poured into water and neutralized with 1 mol/Lhydrochloric acid, and the reaction mixture was extracted with ethylacetate.

The organic layer was washed with water and saturated saline and driedwith anhydrous sodium sulfate. The residue, which was obtained bydistilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: n-hexane/ethyl acetate=1/1to 0/1 (V/V)] to obtain 490 mg (yield: quantitative) of the titlecompound as a white solid.

(9c)(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[5-[(1S)-1-tetrahydropyran-2-yloxyethyl]-1,3,4-oxadiazol-2- yl]spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[5-[(1S)-1-tetrahydropyran-2-yloxyethyl]-,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-N′-[(2S)-2-tetrahydropyran-2-yloxypropanoyl]spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide (0.49 g) of example 9(9b) was dissolved in dichloromethane (5 mL), triethylamine (0.637 mL)and p-toluene sulfonyl chloride (0.209 g) were added, and the mixturewas stirred at room temperature for three hours.

The reaction mixture was poured into water and neutralized with 1 mol/Lhydrochloric acid, and the reaction mixture was extracted with ethylacetate. The organic layer was washed with water and saturated salineand dried with anhydrous sodium sulfate. The residue, which was obtainedby distilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: n-hexane/ethyl acetate=1/1to 0/1 (V/V)] to obtain 452 mg (yield: 95%) of the title compound as awhite solid.

(9d)(2S,5′R)-7-chloro-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[5-[(1S)-1-tetrahydropyran-2-yloxyethyl]-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4′-cyclohex-2-ene]-l′,3-dione (0.452 g) of example 9 (9c)was dissolved in ethanol (4 mL), water (1 mL) and p-toluene sulfonicacid monohydrate (0.0828 g) were added, and the mixture was stirred at50° C. for one hour.

The reaction mixture was poured into water, 1 mol/L hydrochloric acidwas added, and the reaction mixture was extracted with ethyl acetate.The organic layer was washed with water and saturated saline and driedwith anhydrous sodium sulfate. The residue, which was obtained bydistilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: methanol/ethyl acetate=0/1to 1/19 (V/V)] to obtain 119 mg (yield: 31%) of the title compound as awhite solid.

Example 10 (2S,5′R)-7-chloro-6-[5-[(IR)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(10a)(2R)-2-tetrahydropyran-2-yloxypropanehydrazide(2R)-2-tetrahydropyran-2-yloxypropanehydrazide

Methyl (2R)-2-tetrahydropyran-2-yloxypropanoate (CAS Registry Number:124508-74-3, Tetrahedron, 2012, 68, 2068-2073.) (1.6 g) was dissolved inethanol (8 mL), hydrazine monohydrate (1.2 mL) was added, and themixture was stirred at 90° C. for four hours.

After standing at room temperature overnight, the mixture was stirred at90° C. for 10 hours. The mixture was further allowed to stand at roomtemperature overnight and then stirred at 90° C. for 10 hours. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: methanol/ethyl acetate=0/1 to 1/9 (V/V)] to obtain 1 g (yield:62%) of the title compound as a white solid.

(10b)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-N′-[(2R)-2-tetrahydropyran-2-yloxypropanoyl]spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-N′-[(2R)-2-tetrahydropyran-2-yloxypropanoyl]spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide

(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (0.5 g) of example 5 (5a)was dissolved in dichloromethane (10 mL);(2R)-2-tetrahydropyran-2-yloxypropanehydrazide (0.19 g) of example 10(10a), 3H-1,2,3-triazolo [4,5-b]pyridine-3-ol (0.124 g),4-dimethylaminopyridine (0.0112 g), and N,N-diisopropylethylamine (0.478mL) were added; and the mixture was allowed to stand at room temperatureovernight.

The reaction mixture was poured into water and neutralized with 1 mol/Lhydrochloric acid, and the reaction mixture was extracted with ethylacetate. The organic layer was washed with water and saturated salineand dried with anhydrous sodium sulfate. The residue, which was obtainedby distilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: methanol/ethyl acetate=0/10to 1/9 (V/V)] to obtain 460 mg (yield: 94%) of the title compound as awhite solid.

(10c)(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[5-[(1R)-1-tetrahydropyran-2-yloxyethyl]-1,3,4-oxadiazol-2-yl]spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[5-[(1R)-1-tetrahydropyran-2-yloxyethyl]-1,3,4-oxadiazol-2-yl]spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-N′-[(2R)-2-tetrahydropyran-2-yloxypropanoyl]spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide (0.46 g) of example 10(10b) was dissolved in dichloromethane (5 mL), triethylamine (0.598 mL)and p-toluene sulfonyl chloride (0.196 g) were added, and the mixturewas stirred at room temperature for two hours.

The reaction mixture was poured into water and neutralized with 1 mol/Lhydrochloric acid, and the reaction mixture was extracted with ethylacetate. The organic layer was washed with water and saturated salineand dried with anhydrous sodium sulfate. The residue, which was obtainedby distilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: n-hexane/ethyl acetate=1/1to 0/1 (V/V)] to obtain 315 mg (yield: 71%) of the title compound as awhite solid.

(10d)(2S,5′R)-7-chloro-6-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-6-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[5-[(1R)-1-tetrahydropyran-2-yloxyethyl]-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (0.315 g) of example 10(10c) was dissolved in ethanol (4 mL), water (1 mL) and p-toluenesulfonic acid monohydrate (0.0577 g) were added, and the mixture wasstirred at 50° C. for one hour.

The reaction mixture was poured into water, 1 mol/L hydrochloric acidwas added, and the reaction mixture was extracted with ethyl acetate.The organic layer was washed with water and saturated saline and driedwith anhydrous sodium sulfate. The residue, which was obtained bydistilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: methanol/ethyl acetate=0/10to 1/19 (V/V)] to obtain 112 mg (yield: 42%) of the title compound as awhite solid.

Example 11(2S,5′R)-7-chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3′-methoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(11a)(2S,5′R)-7-chloro-4-hydroxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3′-methoxy-5′-methyl-spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-4-hydroxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3′-methoxy-5′-methyl-spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

Magnesium in a scraped form (0.41 g) was added to diethyl ether (60 mL),and iodine (3.9 g) was added in three portions every 20 min. Afterstirring at room temperature for one hour,(2S,5′R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (6.3 g) of example 8 (8b)and toluene (150 mL) were added, and the mixture was stirred at 90° C.for seven hours.

Water was added to the reaction mixture, and after neutralization with 1mol/L hydrochloric acid, the mixture was made weakly basic withsaturated sodium bicarbonate aqueous solution, and the reaction mixturewas extracted with ethyl acetate. The organic layer was washed with 1mol/L hydrochloric acid and saturated saline and dried with anhydroussodium sulfate. The residue, which was obtained by distilling thesolvent under reduced pressure, was purified by silica gel columnchromatography [elution solvent: n-hexane/ethyl acetate=1/1 to 0/1(V/V)] to obtain 2.7 g (yield: 44%) of the title compound as a whitesolid.

(11 b)(2S,5′R)-7-chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3′-methoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3′-methoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-4-hydroxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3′-methoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-l′,3-dione (0.3 g) of example 11 (11a)was dissolved in N,N-dimethylformamide (4 mL); potassium carbonate(0.191 g) and iodoethane (0.0827 mL) were added; and the mixture wasstirred at 80° C. for two hours.

The reaction mixture was poured into water and neutralized with 1 mol/Lhydrochloric acid, and the reaction mixture was extracted with ethylacetate. The organic layer was washed with water and saturated salineand dried with anhydrous sodium sulfate. The residue, which was obtainedby distilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: n-hexane/ethyl acetate=6/4to 1/9 (V/V)] to obtain 42 mg (yield: 13%) of the title compound as awhite solid.

Example 12 (2S,5′R)-7-chloro-4-ethoxy-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3′-methoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-4-ethoxy-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3′-methoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

Magnesium in a scraped form (0.073 g) was added to diethyl ether (20mL), a small amount of iodine (0.70 g) was added, and the mixture wasstirred at room temperature for 10 min. Furthermore, iodine (0.70 g) wasadded in three portions every 20 min. After stirring at room temperaturefor 30 min, toluene (50 mL),(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[5-[(1S)-1-tetrahydropyran-2-yloxyethyl]-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (1.3 g) of example 9 (9c)was added and stirred at 80° C. for eight hours.

Water was added to the reaction mixture, the reaction mixture wasneutralized with 1 mol/L hydrochloric acid, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline and dried with anhydrous sodium sulfate. The residue,which was obtained by distilling the solvent under reduced pressure, wasdissolved in N,N-dimethylformamide (10 mL), potassium carbonate (1.36 g)and iodoethane (0.485 mL) were added, and the mixture was stirred at 80°C. for one hour. The reaction mixture was poured into water andneutralized with 1 mol/L hydrochloric acid, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=7/3 to 2/8 (V/V)], and the obtainedsolid was triturated with n-hexane and ethyl acetate to obtain 122 mg(yield: 13%) of the title compound as a white solid.

Example 13(2S,5′R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(13a)2-tetrahydropyran-2-yloxypropanenitrile2-tetrahydropyran-2-yloxypropanenitrile

2-hydroxypropanenitrile (5.0 g) was dissolved in dichloromethane (150mL), 3,4-dihydro-2H-pyran (7.7 g) and p-toluene sulfonic acidmonohydrate (1.3 g) were added, and the mixture was stirred at roomtemperature for 14 hours. After adding triethylamine to the reactionsolution, the solvent was distilled under reduced pressure, the obtainedresidue was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=97/3 to 7/3 (V/V)], and the titlecompound was obtained as two types of diastereomers that were 5.7 g (lowpolarity, yield: 52%) and 2.5 g (high polarity, yield: 23%),respectively. They were pale yellow solids.

(13b)N′-hydroxy-2-tetrahydropyran-2-yloxy-propanamidineN′-hydroxy-2-tetrahydropyran-2-yloxy-propanamidine

The low polar diastereomer, 2-tetrahydropyran-2-yloxypropanenitrile (5.6g) obtained in example 13 (13a) was dissolved in ethanol (36 mL), 50%hydroxylamine aqueous solution (4.3 mL) was added, and the mixture washeated to 80° C. and stirred for five hours. After returning to roomtemperature, the solvent was distilled under reduced pressure, and theobtained residue was purified by silica gel column chromatography[elution solvent: n-hexane/ethyl acetate=10/1 to 0/1 (V/V)] to obtain5.0 g (yield: 74%) of the title compound as a pale yellow solid.

(13c)[(Z)-(1-amino-2-tetrahydropyran-2-yloxy-propylidene)amino](2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate[(Z)-(1-amino-2-tetrahydropyran-2-yloxy-propylidene)amino](2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate

(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-l′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (0.5 g) of example 5 (5a)was dissolved in dichloromethane (10 mL);N′-hydroxy-2-tetrahydropyran-2-yloxy-propanamidine (0.207 g) of example13 (13b), 3H-1,2,3-triazolo [4,5-b]pyridine-3-ol (0.125 g),4-dimethylaminopyridine (0.0112 g), and N,N-diisopropylethylamine (0.478mL) were added; and the mixture was stirred at room temperature for fivehours.

The reaction mixture was poured into water and neutralized with 1 mol/Lhydrochloric acid, and the reaction mixture was extracted with ethylacetate. The organic layer was washed with water and saturated salineand dried with anhydrous sodium sulfate. The residue, which was obtainedby distilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: n-hexane/ethyl acetate=1/1to 07/1 (V/V)] to obtain 410 mg (yield: 83%) of the title compound as awhite solid.

(13d)(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[3-(1-tetrahydropyran-2-yloxyethyl)-1,2,4-oxadiazol-5-yl]spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[3-(1-tetrahydropyran-2-yloxyethyl)-1,2,4-oxadiazol-5-yl]spiro[benzofuran-2,4′-cyclohex-2-ene]-1l′,3-dione

[(Z)-(1-amino-2-tetrahydropyran-2-yloxy-propylidene)amino](2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (0.41 g) of example 13 (13c)was dissolved in toluene (5 mL) and stirred at 110° C. for seven hours.

The residue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=1/1 to 1/9 (V/V)] to obtain 375 mg(yield: 95%) of the title compound as a white solid.

(13e)(2S,5′R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[3-(1-tetrahydropyran-2-yloxyethyl)-1,2,4-oxadiazol-5-yl]spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (0.375 g) of example 13(13d) was dissolved in ethanol (4 mL), p-toluene sulfonic acidmonohydrate (0.0687 g) and water (1 mL) were added, and the mixture wasstirred at room temperature for eight hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=1/1 to 0/1 (V/V)] to obtain 195 mg(yield: 62%) of the title compound as a white solid.

Example 14(2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(14a)(2S,5′R)-7-chloro-4-hydroxy-3′,6-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-4-hydroxy-3′,6-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

Magnesium in a scraped form (1.03 g) was added to diethyl ether (50 mL),iodine (8.63 g) was added in small portions over one hour. Afterstirring at room temperature for 30 min, toluene (100 mL) and(+)-griseofulvin (10 g) were added, and the mixture was stirred at 80°C. for three hours.

Water was added to the reaction mixture, the mixture was neutralizedwith 1 mol/L hydrochloric acid, and the reaction mixture was extractedwith ethyl acetate. The organic layer was washed with saturated salineand dried with anhydrous sodium sulfate. The residue, which was obtainedby distilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: n-hexane/ethyl acetate=1/1to 0/1 (V/V)] to obtain 7.8 g (yield: 81%) of the title compound as awhite solid.

(14b)(2S,5′R)-7-chloro-3′,6-dimethoxy-5′-methyl-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,6-dimethoxy-5′-methyl-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-4-hydroxy-3′,6-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (5.1 g) of example 14 (14a)was dissolved in N,N-dimethylformamide (60 mL), 2-(2-bromoethoxy)tetrahydro-2H-pyran (3.8 g) and potassium carbonate (6.2 g) were added,and the mixture was stirred at 80° C. for seven hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=8/2 to 3/7 (V/V)] to obtain 6.9 g(yield: 98%) of the title compound as a white solid.

(14c)(2S,5′R)-7-chloro-6-hydroxy-3′-methoxy-5′-methyl-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-6-hydroxy-3′-methoxy-5′-methyl-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-3′,6-dimethoxy-5′-methyl-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (6.9 g) of example 14(14b) was dissolved in pyridine (70 mL), 18-crown 6-ether (4.3 g) andpotassium iodide (2.5 g) were added, and the mixture was stirred at 120°C. for eight hours.

The reaction solution was concentrated, and the reaction mixture waspoured into water and extracted with ethyl acetate. The organic layerwas washed with water and saturated saline and dried with anhydroussodium sulfate. The residue, which was obtained by distilling thesolvent under reduced pressure, was purified by silica gel columnchromatography [elution solvent: n-hexane/ethyl acetate=1/1 to 0/1(V/V)] to obtain 3.8 g (yield: 57%) of the title compound as a whitesolid.

(14d)[(2S,5′R)-7-chloro-1′-methoxy-5′-methyl-3,3′-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate[(2S,5′R)-7-chloro-1′-methoxy-5′-methyl-3,3′-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate

(2S,5′R)-7-chloro-6-hydroxy-3′-methoxy-5′-methyl-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (3.8 g) of example 14(14c) was dissolved in dichloromethane (40 mL), triethylamine (2.9 mL)and N-phenylbis (trifluoromethanesulfonimide) (3.6 g) were added, andthe mixture was allowed to stand at room temperature overnight.

The reaction solution was diluted with dichloromethane, and the organiclayer was washed with water and saturated saline and dried withanhydrous sodium sulfate. The residue, which was obtained by distillingthe solvent under reduced pressure, was purified by silica gel columnchromatography [elution solvent: n-hexane/ethyl acetate=8/2 to 4/6(V/V)] to obtain 3.2 g (yield: 65%) of the title compound as a whitesolid.

(14e)(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′-methoxy-5′-methyl-3,3′-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,6′-cyclohexene]-6-carboxylate(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′-methoxy-5′-methyl-3,3′-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,6′-cyclohexene]-6-carboxylate

[(2S,5′R)-7-chloro-1′-methoxy-5′-methyl-3,3′-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate (1 g)of example 14 (14d) was dissolved in toluene (200 mL); palladium (II)acetate (0.0192 g), 4,5-bis (diphenyl phosphino)-9,9-dimethylxanthene(0.0989 g), and N,N-diisopropylethylamine (0.596 mL) were added; and themixture was heated to 80° C.

2,4,6-trichlorophenyl formate (0.501 g) was added in three portionsevery 10 min. After stirring at 80° C. for 30 min, the reaction mixturewas returned to room temperature, poured into water, and extracted withethyl acetate. The organic layer was washed with water and saturatedsaline and dried with anhydrous sodium sulfate. The residue, which wasobtained by distilling the solvent under reduced pressure, was purifiedby silica gel column chromatography [elution solvent: n-hexane/ethylacetate=8/2 to 4/6 (V/V)] to obtain 850 mg (yield: 75%) of the titlecompound as a white solid.

(14f)(2S,5′R)—N′-acetyl-7-chloro-1′-methoxy-5′-methyl-3,3′-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,6′-cyclohexene]-6-carbohydrazide(2S,5′R)—N′-acetyl-7-chloro-1′-methoxy-5′-methyl-3,3′-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,6′-cyclohexene]-6-carbohydrazide

(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′-methoxy-5′-methyl-3,3′-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,6′-cyclohexene]-6-carboxylate (0.4 g) of example 14(14e) was dissolved in dichloromethane (20 mL); acetohydrazine (purity:90%, 0.0673 g), 3H-1,2,3-triazolo [4,5-b]pyridine-3-ol (0.0824 g),4-dimethylaminopyridine (0.0148 g), and triethylamine (0.254 mL) wereadded; and the mixture was allowed to stand at room temperatureovernight.

The reaction mixture was poured into water and neutralized with 1 mol/Lhydrochloric acid, and the reaction mixture was extracted with ethylacetate. The organic layer was washed with water and saturated salineand dried with anhydrous sodium sulfate. The residue, which was obtainedby distilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: methanol/ethyl acetate=0/10to 1/9 (V/V)] to obtain 280 mg (yield: 86%) of the title compound as awhite solid.

(14g)(2S,5′R)-7-chloro-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)—N′-acetyl-7-chloro-1′-methoxy-5′-methyl-3,3′-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,6′-cyclohexene]-6-carbohydrazide (0.28 g) of example14 (14f) was dissolved in dichloromethane (5 mL), p-toluene sulfonylchloride (0.149 g) and triethylamine (0.364 mL) were added and stirredat room temperature for three hours.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was washed with water and saturated salineand dried with anhydrous sodium sulfate. The residue, which was obtainedby distilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: n-hexane/ethyl acetate=1/1to 0/1 (V/V)] to obtain 202 mg (yield: 75%) of the title compound as awhite solid.

(14h)(2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (0.202 g) of example14 (14g) was dissolved in ethanol (2 mL), p-toluene sulfonic acidmonohydrate (0.037 g) and water (5 mL) were added, and the mixture wasstirred at 50° C. for two hours.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was washed with water and saturated salineand dried with anhydrous sodium sulfate. The residue, which was obtainedby distilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: methanol/ethyl acetate=0/10to 1/9 (V/V)] to obtain 39 mg (yield: 23%) of the title compound as awhite solid.

Example 15(2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(15a)[(Z)-1-aminoethylideneamino](2S,5′R)-7-chloro-1′-methoxy-5′-methyl-3,3′-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,6′-cyclohexene]-6-carboxylate[(Z)-1-aminoethylideneamino](2S,5′R)-7-chloro-1′-methoxy-5′-methyl-3,3′-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,6′-cyclohexene]-6-carboxylate

(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′-methoxy-5′-methyl-3,3′-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,6′-cyclohexene]-6-carboxylate (0.45 g) of example 14(14e) was dissolved in dichloromethane (10 mL);N′-hydroxyethaneimidamide (0.0758 g), 3H-1,2,3-triazolo[4,5-b]pyridine-3-ol (0.0928 g), 4-dimethylaminopyridine (0.00833 g),and triethylamine (0.285 mL) were added; and the mixture was allowed tostand at room temperature overnight.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: methanol/ethyl acetate=0/10 to 1/9 (V/V)] to obtain 345 mg(yield: 94%) of the title compound as a white solid.

(15b)(2S,5′R)-7-chloro-3′-methoxy-5′-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′-methoxy-5′-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[(Z)-1-aminoethylideneamino](2S,5′R)-7-chloro-1′-methoxy-5′-methyl-3,3′-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,6′-cyclohexene]-6-carboxylate (0.345 g) of example15 (15a) was suspended in toluene (5 mL) and stirred at 100° C. for fivehours. The residue, which was obtained by distilling the solvent underreduced pressure, was purified by silica gel column chromatography[elution solvent: n-hexane/ethyl acetate=1/1 to 0/1 (V/V)] to obtain 283mg (yield: 85%) of the title compound as a white solid.

(15c)(2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-3′-methoxy-5′-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-4-(2-tetrahydropyran-2-yloxyethoxy)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (0.283 g) of example15 (15b) was dissolved in ethanol (2 mL), p-toluene sulfonic acidmonohydrate (0.0518 g) and water (5 mL) were added and stirred at 50° C.for three hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: methanol/ethyl acetate=0/10 to 1/9 (V/V)] to obtain 128 mg(yield: 54%) of the title compound as a white solid.

Example 16(2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(16a)(2S,5′R)-7-chloro-4-hydroxy-3′-methoxy-5′-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-4-hydroxy-3′-methoxy-5′-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (2.3 g) of example 7(7b) was dissolved in a mixed solvent of toluene (20 mL) and ether (40mL), magnesium iodide (1.52 g) was added, and the mixture was stirred at80° C. for five hours. Water was added to the reaction mixture, andafter neutralization with 4N hydrochloric acid, the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: petroleum ether/ethyl acetate=1/1 (V/V)] to obtain 1.7 g(yield: 64%) of the title compound as a yellow solid.

(16b)(2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

Palladium chloride (0.45 mg) was dissolved in water (2 mL), andtetrabutylammonium bromide (10.3 mg) and potassium carbonate (4.42 mg)were added. After stirring at 60° C. for 15 minutes,(2S,5′R)-7-chloro-4-hydroxy-3′-methoxy-5′-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (50 mg) of example 16(16a) and oxirane (28.1 mg) were added, and the mixture was stirred at60° C. for 12 hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with dichloromethane. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by thin layer chromatography [developing solvent:ethyl acetate] to obtain 16 mg (yield: 29°/o) of the title compound as ayellow solid.

Example 17(2S,5′R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(17a)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-N′-propanoyl-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-N′-propanoyl-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide

(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (0.50 g) of example 5 (5a)was dissolved in dichloromethane (20 mL), 3H-1,2,3-triazolo[4,5-b]pyridine-3-ol (0.12 g), propionohydrazide (purity: 90%, 0.097 g),4-dimethylaminopyridine (0.011 g), and triethylamine (0.39 mL) wereadded, and the mixture was allowed to stand at room temperatureovernight.

The reaction solution was washed with water and saturated saline anddried with anhydrous sodium sulfate. The solvent was distilled underreduced pressure to obtain 0.75 g of the crude title compound as a paleyellow solid.

(17b)(2S,5′R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3′,4-dimethoxy-5′-methylspiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-N′-propanoyl-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide (0.75 g) of example 17(17a) was dissolved in tetrahydrofuran (10 mL), a (methoxycarbonylsulfamoyl) triethylammonium hydroxide inner salt (0.614 g) was added,and the mixture was stirred at room temperature for three hours.

Water was added to the reaction mixture, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline and dried with anhydrous sodium sulfate. The residue,which was obtained by distilling the solvent under reduced pressure, waspurified by silica gel column chromatography [elution solvent:n-hexane/ethyl acetate=1/1 to 0/1 (V/V)] to obtain 201 mg (yield: 28%,two steps) of the title compound as a pale yellow solid.

Example 18(2S,5′R)-7-chloro-3′4-dimethoxy-5′-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(18a)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-N′-(tetrahydropyran-4-carbonyl)spiro [benzofuran-2,6′-cyclohexene]-6-carbohydrazide(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-N′-(tetrahydropyran-4-carbonyl)spiro [benzofuran-2,6′-cyclohexene]-6-carbohydrazide

(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (0.50 g) of example 5 (5a)was dissolved in dichloromethane (20 mL),tetrahydropyran-4-carbohydrazide (0.20 g), 3H-1,2,3-triazolo[4,5-b]pyridine-3-ol (0.125 g), 4-dimethylaminopyridine (0.011 g,), andtriethylamine (0.38 mL) were added, and the mixture was allowed to standat room temperature overnight.

The reaction solution was washed with water and saturated saline anddried with anhydrous sodium sulfate. The residue, which was obtained bydistilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: methanol/ethyl acetate=0/10to 1/9 (V/V)] to obtain 405 mg (yield: 90%) of the title compound as apale yellow solid.

(18b)(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-N′-(tetrahydropyran-4-carbonyl)spiro [benzofuran-2,6′-cyclohexene]-6-carbohydrazide (0.405 g) ofexample 18 (18a) was dissolved in tetrahydrofuran (10 mL), a(methoxycarbonyl sulfamoyl) triethylammonium hydroxide inner salt (0.392g) was added, and the mixture was stirred at 50° C. for five hours.

Water was added to the reaction mixture, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline and dried with anhydrous sodium sulfate. The residue,which was obtained by distilling the solvent under reduced pressure, waspurified by silica gel column chromatography [elution solvent:n-hexane/ethyl acetate=1/1 to 0/1 (V/V)] to obtain 51 mg (yield: 13%) ofthe title compound as a pale yellow solid.

Example 19(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(19a)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide

(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (20.0 g) of example 5 (5a)was dissolved in dichloromethane (300 mL), and 3H-1,2,3-triazolo[4,5-b]pyridine-3-ol (5.98 g), N,N-diisopropylethylamine (31.9 mL), and4-dimethylaminopyridine (0.447 g) were added. After the mixture wasstirred at room temperature for four hours, hydrazine monohydrate (1.78mL) was added, and the mixture was stirred at room temperature for onehour.

After the reaction solution was concentrated, the residue obtained byazeotroping twice with ethanol was triturated with ethanol to obtain13.2 g (yield: 95%/c) of the title compound as a pale yellow solid.

(19b)(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide (0.50 g) of example 19(19a) was dissolved in tetrahydrofuran (10 mL) and ethanol (10 mL),1-methylpiperidine-4-carboxylic acid (0.225 g),4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride(0.436 g), and 4-methylmorpholine (0.361 mL) were added, and the mixturewas allowed to stand at room temperature for two days.

Thereafter, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinehydrochloride (0.436 g) was added, and the mixture was allowed to standat room temperature overnight.

The reaction mixture was poured into water, and the reaction mixture wasextracted with dichloromethane. The organic layer was washed withsaturated saline and dried with anhydrous sodium sulfate. The solventwas distilled under reduced pressure.

The obtained residue was dissolved in dichloromethane (10 mL),triethylamine (1.45 mL) and p-toluene sulfonyl chloride (0.475 g) wereadded, and the mixture was stirred at room temperature for three hours.

The reaction mixture was poured into water, the mixture was made weaklybasic with saturated sodium bicarbonate aqueous solution, and thereaction mixture was extracted with dichloromethane. The organic layerwas washed with saturated saline and dried with anhydrous sodiumsulfate. The residue, which was obtained by distilling the solvent underreduced pressure, was purified by NH silica gel column chromatography[elution solvent: n-hexane/ethyl acetate=1/1 to 0/1 (V/V)], and theobtained solid was triturated with n-hexane and ethyl acetate to obtain298 mg (yield: 29%, two steps) of the title compound as a white solid.

Example 20(2S,5′R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide (0.50 g) of example 19(19a) was dissolved in tetrahydrofuran (10 mL),4-fluoro-1-methylpiperidine-4-carboxylic acid hydrochloride (0.254 g),4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride(0.436 g), and 4-methylmorpholine (0.361 mL) were added, and the mixturewas allowed to stand at room temperature overnight.

The reaction mixture was poured into water, and the reaction mixture wasextracted with dichloromethane. The organic layer was washed withsaturated saline and dried with anhydrous sodium sulfate. The solventwas distilled under reduced pressure.

The obtained residue was dissolved in dichloromethane (10 mL),triethylamine (1.33 mL) and p-toluene sulfonyl chloride (0.437 g) wereadded, and the mixture was stirred at room temperature for two hours.The reaction mixture was poured into water, and the reaction mixture wasextracted with dichloromethane. The organic layer was washed withsaturated saline and dried with anhydrous sodium sulfate. The residue,which was obtained by distilling the solvent under reduced pressure, waspurified by silica gel column chromatography [elution solvent: ethylacetate/methanol=10/0 to 85/15 (V/V)], and the obtained solid wastriturated with n-hexane and ethyl acetate to obtain 235 mg (yield: 24%,two steps) of the title compound as a white solid.

Example 21 (2S,5′R)-7-chloro-3′,4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(21a)(2S,5′R)-7-chloro-1′,4-dimethoxy-N′-[(2S)-2-methoxypropanoyl]-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide(2S,5′R)-7-chloro-1′,4-dimethoxy-N′-[(2S)-2-methoxypropanoyl]-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide

(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide (0.50 g) of example 19(19a) was dissolved in tetrahydrofuran (10 mL), (S)-(−)-2-methoxypropionic acid (0.164 g) and4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride(0.545 g) were added, and the mixture was allowed to stand at roomtemperature overnight.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: ethyl acetate/methanol=1/0 to 19/1 (V/V)] to obtain 410 mg(yield: 67%) of the title compound as a white solid.

(21b)(2S,5′R)-7-chloro-3′,4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-1′,4-dimethoxy-N′-[(2S)-2-methoxypropanoyl]-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide (0.410 g) of example 21(21a) was dissolved in dichloromethane (5 mL), triethylamine (0.613 mL)and p-toluene sulfonyl chloride (0.200 g) were added, and the mixturewas stirred at room temperature for two hours.

The reaction mixture was poured into water, and after neutralizationwith 1 mol/L hydrochloric acid, the reaction mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedsaline and dried with anhydrous sodium sulfate. The residue, which wasobtained by distilling the solvent under reduced pressure, was purifiedby silica gel column chromatography [elution solvent: n-hexane/ethylacetate=1/1 to 0/1 (V/V)], and the obtained solid was triturated withn-hexane and ethyl acetate to obtain 235 mg (yield: 600/0) of the titlecompound as a white solid.

Example 22 (2S,5′R)-7-chloro-4-ethoxy-3′-methoxy-5′-methyl-6-(5-methyl1,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(22a)(2S,5′R)-7-chloro-4-hydroxy-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-4-hydroxy-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

Magnesium in a scraped form (0.36 g) was added to diethyl ether (50 mL),and iodine (3.5 g) was added in three portions every 15 min. Afterstirring at room temperature for 30 min,(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (5.0 g) of example 5(5c) and toluene (100 mL) were added, and the mixture was stirred at100° C. for six hours.

Water was added to the reaction mixture, and after neutralization with 1mol/L hydrochloric acid, it was extracted with ethyl acetate. Theorganic layer was washed with saturated saline and dried with anhydroussodium sulfate, and the solvent was distilled under reduced pressure toobtain 2.5 g (yield: 52%) of the title compound as a pale yellow solid.

(22b)(2S,5′R)-7-chloro-4-ethoxy-3′-methoxy-5′-methyl-6-(5-methyl1,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-4-ethoxy-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-4-hydroxy-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (200 mg) of example 22(22a) was dissolved in N,N-dimethylformamide (3.0 mL), potassiumcarbonate (283 mg) and iodoethane (0.082 mL) were added, and the mixturewas stirred at 90° C. for five hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=7/3 to 0/10 (V/V)] to obtain 146 mg(yield: 68%) of the title compound as a white solid.

Example 23(2S,5′R)-7-chloro-4-(difluoromethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(23a)(2S,5′R)-7-chloro-4-(difluoromethoxy)-3′,6-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-4-(difluoromethoxy)-3′,6-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-6-hydroxy-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (3.5 g) of example 1 (1a)was dissolved in acetonitrile (70 mL), water (30 mL) and potassiumhydroxide (12 g) were added at −20° C., and the mixture was stirred at−20° C. for 10 min. Diethyl (bromodifluoromethyl) phosphonate (5.5 mL)was slowly added at −20° C., and the temperature was slowly raised to 0°C. over one hour.

Water was added to the reaction mixture, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=8/2 to 2/8 (V/V)] to obtain 2.5 g(yield: 62%) of the title compound as a white solid.

(23b)(2S,5′R)-7-chloro-4-(difluoromethoxy)-6-hydroxy-3′-methoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-4-(difluoromethoxy)-6-hydroxy-3′-methoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-4-(difluoromethoxy)-3′,6-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (2.5 g) of example 23 (23a)was dissolved in pyridine (500 mL), 18-crown-6 (1.9 g) and potassiumiodide (1.1 g) were added, and the mixture was stirred at 120° C. foreight hours. The reaction solution was concentrated, water was added tothe reaction mixture, and after neutralization with 1 mol/L hydrochloricacid, the reaction mixture was extracted with ethyl acetate.

The organic layer was washed with saturated saline and dried withanhydrous sodium sulfate. The residue, which was obtained by distillingthe solvent under reduced pressure, was purified by silica gel columnchromatography [elution solvent: n-hexane/ethyl acetate=1/1 to 0/1(V/V)] to obtain 1.7 g (yield: 71%) of the title compound as apale-yellow solid.

(23c)[(2S,5′R)-7-chloro-4-(difluoromethoxy)-1′-methoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate[(2S,5′R)-7-chloro-4-(difluoromethoxy)-1′-methoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate

(2S,5′R)-7-chloro-4-(difluoromethoxy)-6-hydroxy-3′-methoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (1.7 g) of example 23 (23b)was dissolved in dichloromethane (200 mL), N-phenylbis(trifluoromethanesulfonimide) (1.9 g) and triethylamine (1.6 mL) wereadded, and the mixture was allowed to stand at room temperatureovernight.

The reaction solution was diluted with dichloromethane, and the organiclayer was washed with water and saturated saline and dried withanhydrous sodium sulfate. The residue, which was obtained by distillingthe solvent under reduced pressure, was purified by silica gel columnchromatography [elution solvent: n-hexane/ethyl acetate=10/0 to 6/4(V/V)] to obtain 950 mg (yield: 41%) of the title compound as a whitesolid.

(23d)(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-4-(difluoromethoxy)-1′-methoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate2,4,6-trichlorophenyl(2S,5′R)-7-chloro-4-(difluoromethoxy)-1′-methoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate

[(2S,5′R)-7-chloro-4-(difluoromethoxy)-l′-methoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate (0.40 g) ofexample 23 (23c) was dissolved in toluene (5 mL); palladium (II) acetate(0.018 g), 4,5-bis (diphenyl phosphino)-9,9-dimethylxanthene (0.091 g),and N,N-diisopropylethylamine (0.275 mL) were added; and the mixture washeated to 80° C. 2,4,6-trichlorophenyl formate (0.231 g) was added inthree portions every 30 min.

After stirring at 80° C. for 30 min, the reaction mixture was pouredinto water, and the reaction mixture was extracted with ethyl acetate.The organic layer was washed with water and saturated saline and driedwith anhydrous sodium sulfate. The residue, which was obtained bydistilling the solvent under reduced pressure, was purified by silicagel column chromatography [elution solvent: n-hexane/ethyl acetate=10/0to 6/4 (V/V)] to obtain 182 mg (yield: 40%) of the title compound as awhite solid.

(23e)(2S,5′R)—N′-acetyl-7-chloro-4-(difluoromethoxy)-1′-methoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide(2S,5′R)—N′-acetyl-7-chloro-4-(difluoromethoxy)-1′-methoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide

(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-4-(difluoromethoxy)-l′-methoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (0.182 g) of example 23(23d) was dissolved in dichloromethane (20 mL); acetohydrazide (purity:90%, 0.035 g), 3H-1,2,3-triazolo [4,5-b]pyridine-3-ol (0.043 g),4-dimethylaminopyridine (0.0038 g), and triethylamine (0.131 mL) wereadded; and the mixture was allowed to stand at room temperatureovernight.

The reaction mixture was added to water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=10/0 to 7/3 (V/V)] to obtain 141 mg(yield: 98%) of the title compound as a white solid.

(23f)(2S,5′R)-7-chloro-4-(difluoromethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-4-(difluoromethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)—N′-acetyl-7-chloro-4-(difluoromethoxy)-1′-methoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbohydrazide (0.141 g) of example 23(23e) was dissolved in 1,4-dioxane (5.0 mL), a (methoxycarbonylsulfamoyl) triethylammonium hydroxide inner salt (0.146 g) was added,and the mixture was stirred at room temperature for two hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=10/0 to 4/6 (V/V)] to obtain 70 mg(yield: 52%) of the title compound as a white solid.

Example 24(2S,5′R)-7-chloro-3′,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(24a)[(Z)-(1-amino-2-methoxy-propylidene)amino](2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate[(Z)-(1-amino-2-methoxy-propylidene)amino](2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate

(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (0.5 g) of example 5 (5a)was dissolved in dichloromethane (10 mL);N′-hydroxy-2-methoxypropanimidamide (0.130 g), 3H-1,2,3-triazolo[4,5-b]pyridine-3-ol (0.125 g), 4-dimethylaminopyridine (0.011 g), andN,N-diisopropylethylamine (0.478 mL) were added; and the mixture wasstirred at room temperature for three hours.

The reaction mixture was poured into water, and after neutralizationwith 1 mol/L hydrochloric acid, the reaction mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedsaline and dried with anhydrous sodium sulfate. The residue, which wasobtained by distilling the solvent under reduced pressure, was purifiedby silica gel column chromatography [elution solvent: n-hexane/ethylacetate=1/1 to 0/1 (V/V)] to obtain 375 mg (yield: 88%) of the titlecompound as a white solid.

(24b)(2S,5′R)-7-chloro-3′,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[(Z)-(1-amino-2-methoxy-propylidene)amino](2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (0.375 g) of example 24(24a) was dissolved in toluene (10 mL), and the mixture was stirred at120° C. for 12 hours.

The residue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=10/0 to 7/3 (V/V)], and trituration wascarried out with n-hexane and ethyl acetate to obtain 265 mg (yield:74%) of the title compound as a white solid.

Example 25(2S,5′R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(25a)[(Z)-(1-amino-2-hydroxy-2-methyl-propylidene)amino](2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate[(Z)-(1-amino-2-hydroxy-2-methyl-propylidene)amino](2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate

(2,4,6-trichlorophenyl)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (1.0 g) of example 5 (5a)was dissolved in dichloromethane (20 mL);2,N-dihydroxy-2-methyl-propionamizine (0.238 g), 3H-1,2,3-triazolo[4,5-b]pyridine-3-ol (0.249 g), 4-dimethylaminopyridine (0.022 g), andN,N-diisopropylethylamine (0.957 mL) were added; and the mixture wasallowed to stand at room temperature overnight.

The reaction mixture was poured into water and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: ethyl acetate/methanol=10/0 to 9/1 (V/V)] to obtain 765 mg(yield: 89%) of the title compound as a white solid.

(25b)(2S,5′R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[(Z)-(1-amino-2-hydroxy-2-methyl-propylidene)amino](2S,5′R)-7-chloro-l′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carboxylate (0.765 g) of example 25(25a) was dissolved in toluene (10 mL), and the mixture was stirred at110° C. for seven hours.

The residue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=1/1 to 0/1 (V/V)], and trituration wascarried out with n-hexane and ethyl acetate to obtain 512 mg (yield:70%) of the title compound as a white solid.

Example 26(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(1H-pyrazol-5-yl) spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(26a)(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(2-tetrahydropyran-2-ylpyrazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(2-tetrahydropyran-2-ylpyrazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate (2.0 g) ofexample 3 (3a) was dissolved in 1,4-dioxane (30 mL) and water (2 mL);1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.54 g), potassium carbonate (1.76 g), and [1,1′-bis (diphenylphosphino) ferrocene]palladium (II) dichloride (0.155 g) were added atroom temperature; and the mixture was stirred at 90° C. for three hours.

After the reaction temperature was returned to room temperature, theinsoluble substances were filtered. The filtrate was poured into waterand extracted with dichloromethane. The organic layer was washed withsaturated saline and dried with anhydrous sodium sulfate. The residue,which was obtained by distilling the solvent under reduced pressure, waspurified by silica gel column chromatography [elution solvent: petroleumether/ethyl acetate=10/1 to 2/1 (V/V)] to obtain 1.8 g (yield: 90%) ofthe title compound as a pale yellow solid.

(26b)(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(1H-pyrazol-5-yl) spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(1H-pyrazol-5-yl) spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(2-tetrahydropyran-2-ylpyrazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (1.8 g) of example 26(26a) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5mL) was added, and the mixture was stirred at room temperature for 20minutes.

The reaction mixture was poured into water, and the reaction mixture wasextracted with dichloromethane. The organic layer was washed withsaturated saline and dried with anhydrous sodium sulfate. The residue,which was obtained by distilling the solvent under reduced pressure, waspurified by high performance liquid chromatography [elution solvent:0.05% hydrochloric acid/acetonitrile=70/30 to 45/55 (V/V)] to obtain 1.1g (yield: 74%) of the title compound as a yellow solid.

Example 27 (2S,5′R)-7-chloro-3′,4-dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(1H-pyrazol-5-yl) spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione (250 mg) of example 26 (26b)was dissolved in N,N-dimethylformamide (5 mL), 2-bromoethyl methyl ether(179 mg) and potassium carbonate (267 mg) were added, and the mixturewas stirred at 80° C. for three hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with dichloromethane. The organic layer was washed withsaturated saline and dried with anhydrous sodium sulfate. The residue,which was obtained by distilling the solvent under reduced pressure, waspurified by high performance liquid chromatography [elution solvent: 10mM ammonium hydrogen carbonate aqueous solution/acetonitrile=67/33 to37/63 (V/V)] to obtain 81 mg (yield: 28%) of the title compound as awhite solid.

Example 28 (2S,5′R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(28a)(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbaldehyde(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbaldehyde

[(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate (4.5 g) ofexample 3 (3a) was dissolved in 1,4-dioxane (120 mL), tributylstannylmethanol (CAS Registry Number: 27490-33-1) (8.29 g) and tetrakistriphenyl phosphine palladium (1.66 g) were added at room temperature,and the mixture was stirred at 60° C. for 15 hours.

The residue, which was obtained by distilling the solvent under reducedpressure, was roughly purified by silica gel column chromatography[elution solvent: petroleum ether/ethyl acetate=25/1 to 1/1 (V/V)].

The obtained crude product was dissolved in dichloromethane (20 mL),Dess-Martin Periodinane (3.61 g) was added, and the mixture was stirredat room temperature for two hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with dichloromethane. The organic layer was washed withsaturated saline and dried with anhydrous sodium sulfate. The residue,which was obtained by distilling the solvent under reduced pressure, waspurified by silica gel column chromatography [elution solvent: petroleumether/ethyl acetate=1/1 (V/V)] to obtain 1.25 g (yield: 37%, two steps)of the title compound as a yellow solid.

(28b)(2S,5′R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbaldehyde (1.0 g) of example 28 (28a)was dissolved in methanol (10 mL), hydroxylamine hydrochloride (158 mg)and sodium acetate (585 mg) were added, and the mixture was stirred atroom temperature for one hour.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline and dried with anhydrous sodium sulfate. The residue,which was obtained by distilling the solvent under reduced pressure, wasroughly purified by silica gel column chromatography [elution solvent:petroleum ether/ethyl acetate=50/1 to 10/1 (V/V)], and a crude product(730 mg) containing(2S,5′R,6E)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbaldehyde oxime as a main componentwas obtained as a yellow solid.

The obtained crude product (300 mg) was dissolved in dichloromethane (6mL); 4-methylenete trahydropyran (CAS Registry Number: 36838-71-8) (322mg), pyridine (0.041 mL), and sodium hypochlorite (20 mL) were added at−10° C., and the mixture was stirred at room temperature for threehours.

The reaction mixture was poured into water and the reaction mixture wasextracted with dichloromethane. The organic layer was washed withsaturated saline and dried with anhydrous sodium sulfate. The residue,which was obtained by distilling the solvent under reduced pressure, waspurified by high performance liquid chromatography [elution solvent:0.225% formic acid aqueous solution/acetonitrile=55/45 to 45/55 (V/V)]to obtain 92 mg (yield: 17%, two steps) of the title compound as a whitesolid.

Example 29(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl) spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl) spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

The crude product (92 mg) containing(2S,5′R,6E)-7-chloro-l′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-carbaldehyde oxime, which was obtainedas an intermediate in example 28 (28b), as the main component wasdissolved in dichloromethane (3.0 mL); tert-butyl 4-methylenepiperidine-1-carboxylate (CAS Registry Number: 159635-49-1) (162 mg),pyridine (0.013 mL), and sodium hypochlorite (7.0 mL) were added at −10°C. and the mixture was stirred at −10° C. for three hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with dichloromethane. The organic layer was washed withsaturated saline and dried with anhydrous sodium sulfate. The residue,which was obtained by distilling the solvent under reduced pressure, wasroughly purified by silica gel column chromatography [elution solvent:petroleum ether/ethyl acetate=1/1 (V/V)].

The obtained crude product was dissolved in dichloromethane (4.0 mL),and a 1,4-dioxane solution of hydrogen chloride (4 M, 50 mL) was added.After stirring at room temperature for two hours, the solvent wasdistilled under reduced pressure.

The obtained residue was dissolved in methanol (1.0 mL); formaldehyde(70 mg), triethylamine (0.078 mL), acetic acid (0.065 mL), and sodiumcyanoborohydride (55 mg) were added; and the mixture was stirred at roomtemperature for three hours.

The residue, which was obtained by distilling the solvent under reducedpressure, was purified by high performance liquid chromatography[elution solvent: 0.05% ammonia aqueous solution/acetonitrile=67/33 to37/63 (V/V)] to obtain 41 mg (yield: 32%, three steps) of the titlecompound as a white solid.

Example 30(2S,5′R)-7-chloro-3′,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[(2S,5′R)-7-chloro-l′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate (0.50 g) ofexample 3 (3a) was dissolved in toluene (10 mL);2-methoxy-5-pyrimidylboronic acid (0.245 g), saturated sodiumbicarbonate aqueous solution (5.0 mL), and chloro (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium (II) (0.167 g) were added at roomtemperature; and the mixture was stirred at 90° C. for two hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=7/3 to 1/9 (V/V)] to obtain 58 mg(yield: 12%) of the title compound as a pale yellow solid.

Example 31(2S,5′R)-7-chloro-3′,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate (0.50 g) ofexample 3 (3a) was dissolved in toluene (10 mL);2-methoxypyridine-5-boronic acid (0.244 g), saturated sodium bicarbonateaqueous solution (5.0 mL), and chloro (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium (II) (0.167 g) were added at roomtemperature; and the mixture was stirred at 90° C. for two hours.

The reaction mixture was poured into water, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried with anhydrous sodium sulfate. Theresidue, which was obtained by distilling the solvent under reducedpressure, was purified by silica gel column chromatography [elutionsolvent: n-hexane/ethyl acetate=1/1 to 0/1 (V/V)] to obtain 128 mg(yield: 28%) of the title compound as a pale yellow solid.

Example 32 (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(3-pyridyl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(3-pyridyl) spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione

[(2S,5′R)-7-chloro-1′,4-dimethoxy-5′-methyl-3,3′-dioxo-spiro[benzofuran-2,6′-cyclohexene]-6-yl]trifluoromethanesulfonate (0.50 g) ofexample 3 (3a) was dissolved in N,N-dimethylformamide (5.0 mL);3-pyridyl boronic acid (0.196 g), [1,1′-bis (diphenyl phosphino)ferrocene]palladium (II) dichloride (0.347 g), and sodium bicarbonate(0.268 g) were added; and the mixture was stirred at 70° C. for threehours.

The reaction mixture was poured into water, the reaction mixture wasextracted with ethyl acetate, and the insoluble substances were removedby celite filtration. The organic layer was washed with water andsaturated saline and dried with anhydrous sodium sulfate. The residue,which was obtained by distilling the solvent under reduced pressure, waspurified by silica gel column chromatography [elution solvent:n-hexane/ethyl acetate=171 to 0/1 (V/V)] to obtain 65 mg (yield: 15%) ofthe title compound as a pale yellow solid.

The results of analyzing the compounds of the examples by powder X-raydiffraction are shown below.

Analysis conditions:

-   -   Model: Rigaku Rint TTR-III    -   Sample holder: Non-reflective sample holder    -   Sample: Appropriate amount    -   X-ray generation conditions: 50 kV, 300 mA    -   Wavelength: 1.54 Å (copper Ka radiation)    -   Scanning speed: 20°/min    -   Scanning range: 2 to 40°    -   Sampling width: 0.02°

Analysis operation: Several mg of the test substance was collected witha spatula, placed on a non-reflective sample holder, and flattened witha piece of weighing paper. Thereafter, peak patterns were analyzed underthe conditions described above.

Example 4

When the maximum peak intensity is set to 100 in FIG. 1 of thediffraction pattern of powder X-ray diffraction (CuKα, λ=1.54 Å,scanning speed=20°/min), peaks with relative intensities of 4 or moreare shown in Table 2.

TABLE 2 Peak d Relative No. 2θ value Intensity 1 9.50 9.30 100 2 10.748.23 35 3 14.08 6.28 56 4 16.36 5.41 32 5 17.88 4.96 32 6 23.30 3.81 327 23.62 3.76 34 8 23.94 3.71 44 9 24.42 3.64 35 10 27.16 3.28 33

Example 5

When the maximum peak intensity is set to 100 in FIG. 2 of thediffraction pattern of powder X-ray diffraction (CuKα, λ=1.54 Å,scanning speed=20°/min), peaks with relative intensities of 4 or moreare shown in Table 3.

TABLE 3 Peak d Relative No. 2θ value Intensity 1 9.98 8.86 24 2 12.287.20 100 3 15.62 5.67 29 4 18.28 4.85 64 5 19.12 4.64 21 6 20.68 4.29 227 22.30 3.98 38 8 22.90 3.88 23 9 24.16 3.68 24 10 29.28 3.05 18

Example 17

When the maximum peak intensity is set to 100 in FIG. 3 of thediffraction pattern of powder X-ray diffraction (CuKα, λ=1.54 Å,scanning speed=20°/min), peaks with relative intensities of 4 or moreare shown in Table 4.

TABLE 4 Peak d Relative No. 2θ value Intensity 1 6.42 13.76 72 2 11.167.92 100 3 11.58 7.64 87 4 12.72 6.95 68 5 14.68 6.03 83 6 16.96 5.22 617 19.62 4.52 60 8 22.40 3.97 43 9 24.14 3.68 48 10 25.96 3.43 45

Example 25

When the maximum peak intensity is set to 100 in FIG. 4 of thediffraction pattern of powder X-ray diffraction (CuKα, λ=1.54 Å,scanning speed=20°/min), peaks with relative intensities of 4 or moreare shown in Table 5.

TABLE 5 Peak d Relative No. 2θ value Intensity 1 8.08 10.93 57 2 11.487.70 28 3 13.20 6.70 32 4 13.54 6.53 100 5 14.04 6.30 22 6 14.44 6.13 357 20.76 4.28 21 8 21.42 4.14 20 9 22.34 3.98 28 10 25.28 3.52 49

The structural formulas of the compounds described in examples and theirphysicochemical data are summarized below.

TABLE 6 Example No. Structural formula Physicochemical data 1(1a)

¹H NMR(400 MHz, DMSO-d₆): δ (ppm) = 12.04 (1H, brs), 6.28(1H, s),5.59(1H, s), 3.81(3H, s), 3.63(3H, s), 2.83-2.73(1H, m), 2.68(1H, dd, J= 16.6, 13.2 Hz), 2.34(1H, dd, J = 16.6, 4.9 Hz), 0.81(3H, d, J = 6.8Hz). 1(1b)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 6.15 (1H, s), 5.55(1H, s), 4.28(2H, t,J = 4.8 Hz), 4.10-4.04 (2H, m), 3.97 (3H, s), 3.65(3.H, s), 3.04 (1H,dd, J = 16.6, 13.2 Hz), 2.89-2.80(1H, m), 2.44(1H, dd, J = 16.6, 4.9Hz),2.10(1H, t, J = 6.4Hz), 0.97 (3H, d, J = 6.4Hz), MS(ESI) m/z: 383 (M +H)⁺ 2

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 6.19(1H, s), 5.54(1H, s), 4.31(2H, t,J = 4.4Hz), 3.95(3H, s), 3.85(2H, t, J = 4.4 Hz), 3.61(3H, s), 3.50(3H,s), 3.04(1H, dd, J = 16.6, 13.7 Hz), 2.89-2.79(1H, m), 2.43(1H, dd, J =16.6, 4.4Hz), 0.95(3H, d, J = 6.8Hz). MS(ESI) m/z: 397 (M + H)⁺ 3(3a)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 6.54(1H, s), 5.58(1H, s), 3.99(3H, s),3.65(3H, s), 2.97(1H, dd, J = 16.6, 13.2 Hz), 2.93-2.81(1H, m), 2.48(1H, dd, J = 16.1, 4.4 Hz), 0.98(3H, d, J = 6.8 Hz). 3(3b)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.49(1H, d, J = 2.4 Hz), 7.12(1H, s),7.01(1H, d, J = 2.4 Hz), 5.57)1H, s), 4.02(3H, s), 4.02(3H, s), 3.63(3H, s), 3.05(1H, dd, J = 16.6, 13.3 Hz), 2.95- 2.82(1H, m), 2.46(1H,dd, J = 16.6, 4.3 Hz), 0.99 (3H, d, J = 6.7 Hz). MS(ESI) m/z: 403 (M +H)⁺ 4

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.53(1H, d, J = 2.4 Hz), 7.14(1H, s),7.01(1H, d, J = 2.4 Hz), 5.57(1H, s), 4.29(2H, q, J = 7.3 Hz), 4.03 (3H,s), 3.64(3H, s), 3.05(1H, dd, J = 16.6, 13.3 Hz), 2.94-2.83(1H, m),2.47(1H, dd, J = 16.6, 4.9 Hz), 1.58(3H, t, J = 7.3 Hz), 1.00(3H, d, J =6.4 Hz). MS(ESI) m/z: 417 (M + + H) 5(5a)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.48(2H, s), 7.23(1H, s), 5.59(1H, s),4.05(3H, s), 3.65(3H, s), 3.00 (1H, dd, J = 16.1, 13.2 Hz),2.95-2.82(1H, m), 2.50(1H, dd, J = 16.1, 4.4 Hz), 1.00 (3H, d, J = 6.8Hz).

TABLE 7 Example No. Structural formula Physicochemical data 5(5b)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 9.00 (1H, brd, J = 5.4 Hz), 8.59(1H,brd, J = 5.4 Hz), 6.88 (1H, s), 5.58(1H, s), 4.00(3H, s), 3.64(3H, s),2.99 (1H, dd, J = 16.6, 13.2 Hz), 2.92-2.83(1H, m), 2.48(1H, dd, J =16.6, 4.4 Hz), 2.17(3H, s,), 0.96(3H, d, J = 6.4Hz). 5(5c)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.23 (1H, s), 5.59(1H, s), 4.04(3H,s), 3.65(3H, s), 3.05-2.97(1H, m), 2.98-2.86(1H, m), 2.71(3H, s),2.53-2.45(1H, m), 1.00(3H, d, J = 6.9 Hz). MS(ESI) m/z: 405 (M + H)^(+.)6(6a)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 6.96 (1H, s), 5.57(1H, s), 5.03 (2H,brs), 4.00(3H, s), 3.64 (3H, s), 3.00(1H, dd, J = 16.6, 13.2 Hz),2.93-2.83(1H, m), 2.48(1H, dd, J = 16.6, 4.4 Hz), 2.08(3H, s), 0.98(3H,d, J = 6.4 Hz). 6(6b)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.24 (1H, s), 5.59(1H, s), 4.05(3H,s), 3.65(3H, s), 3.00(1H, dd, J = 16.6, 13.2 Hz), 2.96- 2.86(1H, m),2.56(3H, s), 2.50(1H, dd, J = 16.6, 4.4 Hz), 1.00 (3H, d, J = 6.6 Hz).MS(ESI) m/z: 405 (M + H)⁺ 7(7a)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 6.82 1H, s), 5.58(1H, s), 4.00(3H, s),3.63(3H, s), 2.96 (1H, dd, J = 16.1, 13.2 Hz), 2.92-2.83 (1H, m),2.49(1H, dd, J = 16.1, 3.9 Hz), 0.97 (3H, d, J = 6.4 Hz). 7(7b)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.12 (1H, s), 5.57(1H, s), 4.02(3H,s), 3.64(3H, s), 3.02(1H, dd, J = 16.6, 13.2 Hz), 2.95- 2.85(1H, m),2.73 (3H, s), 2.48(1H, dd, J = 16.6, 4.4 Hz), 1.00(3H, d, J =6.6 Hz).MS(ESI) m/z: 405 (M + H)⁺

TABLE 8 Example No. Structural formula Physicochemical data 8(8a)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 9.39 (1H, brs), 8.83 (1H, brs), 6.91(1H, s), 5.57 (1H, s), 4.00(3H, s), 3.64(3H, s), 3.00(1H, dd, J = 16.6,13.2 Hz), 2.93-2.82(1H, m), 2.47(1H, dd, J = 16.6, 4.4 Hz), 2.43(1H,brs), 1.57 (6H, s), 0.97(3H, d, J = 6.4 Hz). 8(8b)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.25 (1H, s), 5.59(1H, s), 4.05(3H,s), 3.64 (3H, s), 3.01(1H, dd, J = 16.1, 13.2 Hz), 2.97-2.83(1H, m),2.52(1H, m), 2.49(1H, dd, J = 16.1, 4.4 Hz), 1.81(6H, s), 1.00(3H, d, J= 6.4 Hz). MS(ESI) m/z: 449 (M + H)⁺ 9(9a)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.89(0.3H, brs), 7.60 (0.7H, brs),4.65-4.60(1H, m), 4.35-4.28(1H, m), 3.92-3.81 (3H, m), 3.55-3.46(1H, m),1.90-1.72 (2H, m), 1.65-1.52 (4H, m), 1.48(2.1H, d, J = 6.8 Hz),1.41(0.9H, J = 6.8 Hz). 9(9b)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 9.71(0.2H, d, J = 6.8 Hz), 9.18 (0.8H,d, J = 5.9 Hz), 8.94(0.2H, d, J = 6.4 Hz), 8.90 (0.8H, d, J = 5.9Hz),6.93(0.2H, s), 6.92(0.8H, s), 6.58(0.2H, s), 4.81-4.76(0.8H, m),4.72-4.68 (0.2H, m), 4.50-4.41(1H, m), 3.99(3H, s), 3.97-3.90(1H, m),3.58-4.54(4H, m), 3.00(1H, dd, J = 16.2, 13.2 Hz), 2.93-2.84(1H, m),2.48(1H, dd, J = 16.2, 4.4 Hz), 1.96-1.46 (9H, m), 0.98(3H, d, J = 6.8Hz). 9(9c)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.26(1H, s), 5.58(1H, s), 5.26(0.8H,q, J = 6.4 Hz), 5.17(0.2H, q, J = 6.4 Hz), 4.93- 4.89(0.2H, m),4.85-4.80(0.8H, m), 4.04(3H, s), 3.97-3.90(0.8H, m), 3.88-3.81(0.2H, m),3.64 (3H, s), 3.63-3.57 (0.8H, m), 3.50-3.42(0.2H, m), 3.01(1H, dd, J =16.2, 13.2 Hz), 2.95-2.85(1H, m), 2.49(1H, dd, J = 16.2, 4.4 Hz),1.92-1.80 (1H, m), 1.78- 1.69(5H, m), 1.68-1.50(3H, m), 1.00(3H, d, J =6.4 Hz). 9(9d)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.24(1H, s), 5.58(1H, s), 5.26(1H,quintet J = 6.4 Hz), 4.04(3H, s), 3.64(3H, s), 3.01 (1H, dd, J = 16.6,13.7 Hz), 2.95-2.85(1H, m), 2.55(1H, brs), 2.49(1H, dd, J = 16.6, 4.4Hz), 1.78(3H, d, J = 6.4 Hz, 1.00(3H, d, J = 6.8 Hz). MS(ESI) m/z: 435(M + H)⁺

TABLE 9 Example No. 1 Structural formula Physicochemical data 10(10a)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.89(0.3H, brs), 7.60(0.7H, brs),4.67-4.60(1H, m), 4.36-4.27 (1H, m), 3.96-3.78(3H, m), 3.57-3.46(1H, m),1.91-1.72 (2H, m), 1.65-1.52(4H, m), 1.48(2.1H, d, J = 6.8 Hz),1.42(0.9H, d, J = 6.8 Hz). 10(10b)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 9.72(0.3H, d, J = 6.4 Hz), 9.19(0.7H,d, J = 6.4 Hz), 9.00(0.3H, d, J = 6.4 Hz), 8.96(0.7H, d, J = 6.4 Hz),6.93(0.3H, s), 6.92(0.7H, s), 5.57(1H, s), 4.83-4.76(0.7H, m),4.74-4.67(0.3H, m), 4.52-4.40(1H, m), 4.07- 3.88(4H, m), 3.71-3.53(4H,m), 3.06-2.82(2H, m), 2.48(1H, dd, J = 16.6, 4.4 Hz), 1.98-1.45 (9H, m),0.97(3H, d, J = 6.4 Hz). 10(10c)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.27(1H, s), 5.58(1H, s), 5.30(0.7H,q, J = 6.8 Hz), 5.16(0.3H, q, J = 6.8 Hz), 4.93-4.89(0.3H, m), 4.85-4.80(0.7H, m), 4.04(3H, s), 3.97-3.90(0.7H, m), 3.89-3.81 (0.3H, m),3.64(3H, s), 3.63-3.56(0.7H, m), 3.50- 3.41(0.3H, m), 3.05-2.85(2H, m),2.53-2.45(1H, m), 1.93-1.46(9H, m), 0.99(3H, d, J = 6.8 Hz). 10(10d)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.24(1H, s), 5.58(1H, s), 5.26(1H,quintet J = 6.8 Hz), 4.04 (3H, s), 3.64(3H, s), 3.01(1H, dd, J = 16.2,13.2 Hz), 2.95-2.85(1H, m), 2.56(1H, brs), 2.49(1H, dd, J = 16.6 4.4Hz), 1.78 (3H, d, J = 6.8 Hz), 1.00 (3H, d, J = 6.8 Hz). \MS(ESI) m/z:435 (M + H)⁺ 11(11a)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.28 (1H, s), 5.61(1H, s), 4.04(1H,s), 3.68(3H, s), 3.05-2.87 (2H, m), 2.59-2.52 (1H, m), 1.80(6H, s),1.02(3H, d, J = 6.4 Hz). 11(11b)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.22(1H, s), 5.57(1H, s),4.31-4.23(2H, m), 3.64(3H, s), 3.02 (1H, dd, J = 16.6, 13.7 Hz),2.95-2.85(1H, m), 2.56-2.42(2H, m), 1.81 (6H, s), 1.54(3H, t, J = 6.8Hz), 1.00(3H, d, J = 6.4 Hz). MS(ESI) m/z: 463 (M+ H)⁺

TABLE 10 Example No. Structural formula Physicochemical data 12

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.22(1H, s), 5.57(1H, s),5.31-5.25(1H, m), 4.32-4.22(2H, m), 3.54(3H, s), 3.03(1H, dd, J = 16.6,13.2 Hz), 2.96- 2.85(1H, m), 2.52-2.44(2H, m), 1.78(3H, d, J = 6.4 Hz),1.54(3H, t, J = 6.8 Hz), 1.00(3H, d, J = 6.4 Hz). MS(ESI) m/z: 449 (M +H)⁺ 13(13a)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 4.93-4.86(1H, m), 4.65(1H, q, J = 6.8Hz), 3.82-3.72(1H, m), 3.60- ¹H NMR(400 MHz, CDCl₃): δ (ppm) =4.81-4.77(1H m), 4.39(1H, q, J = 6.8 Hz), 3.97(1H, td, J = 11.7, 2.9Hz), 3.67-3.60(1H, m), 1.90-1.52(9H, m). 13(13b)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.70(1H, brs), 4.70 (2H, brs),4.63-4.58(1H, m), 4.36(1H, q, J = 6.8 Hz), 3.93-3.83(1H, m),3.56-3.48(1H, m), 1.90-1.78(1H, m), 1.75-1.66(1H, m), 1.63-1.49(4H m),1.44(3H, d, J = 6.8 Hz). 13(13c)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 6.97 (1H, brs), 5.57(1H, s), 5.21(2H,brs), 4.78-4.61(2H, m), 4.00(3H, s), 3.94-3.85(1H, m), 3.63(3H, s),3.59- 3.51(1H, m), 3.00(1H, dd, J = 16.6, 13.7 Hz), 2.93- 2.82(1H, m),2.48(1H, dd, J = 16.6, 4.4 Hz), 1.90- 1.79(1H, m), 1.78-1.69(1H, m),1.63-1.49(7H, m), 0.98(3H, d, J = 6.8 Hz). 13(13d)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.247(1H, s), 5.58(1H, s), 5.23(1H, q,J = 6.8 Hz), 4.79-4.70(1H, m), 4.05(3H, s), 3.99-3.92(1H, m), 3.63(3H,s), 3.62-3.56(1H, m), 3.00(1H, dd, J = 16.6, 13.7 Hz), 2.95-2.85(1H, m),2.49(1H, dd, J = 16.6, 4.4 Hz), 1.94-1.83(1H, m), 1.78-1.50(8H, m),0.99(3h, d, J = 6.8 Hz). 13(13e)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.25(1H, s), 5.58(1H, s), 5.17(1H,quintet, J = 6.8 Hz), 4.06(3H, s), 3.64(3H, s), 3.00(1H, dd, J = 16.6,13.2 Hz), 2.96- 2.85(1H, m), 2.50(1H, dd, J = 16.6, 4.4 Hz), 2.48-2.43(1H, m), 1.73(3H, d, J = 6.8 Hz), 1.00(3H, d, J = 6.4 Hz). MS(ESI)m/z: 435 (M + H)⁺.

TABLE 11 Example No. Structural formula Physicochemical data 14(14a)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.76(1H, brs), 6.19(1H, s), 5.57(1H,s), 3.98(3H, s), 3.66 (3H, s), 3.00-2.82(2H, m), 2.49(1H, dd, J = 16.6,4.4 Hz), 0.99 (3H, d, J = 6.4 hz). 14(14b)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 6.26(1H, s), 5.54(1H, s),4.75-4.69(1H, m), 4.40-4.29(2H, m), 4.15-4.08(1H, m), 4.00(3H, s),3.96-3.85(2H, m), 3.62 (3H, s), 3.57-3.50(1H, m), 3.03(1H, dd, J = 16.6,13.2 Hz), 2.89-2.79(1H, m), 2.46-2.39 (1H, m), 1.88-1.68(2H, m),1.62-1.45(4H, m), 0.96(3H, d, J = 6.8 Hz). 14(14c)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 6.30 (1H, s), 5.54(1H, s),4.78-4.71(1H, m), 4.30-4.21(2H, m), 4.12-4.04(1H, m), 3.95-3.84(2H, m),3.63(3H, s), 3.57-3.50(1H, m), 3.04(1H, dd, J = 16.6, 13.2 Hz),2.88-2.77(1H, m), 2.46-2.39 (1H, m), 1.85-1.47(6H, m), 0.97 (3H, d, J =6.8 Hz). 14(14d)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 6.67(1H, s), 5.57(1H, s),4.75-4.70(1H, m), 4.37-4.28(2H, m), 4.15-4.07(1H, m), 3.93-3.84(2H, m),3.65(3H, s), 3.57-3.51(1H, m), 3.01-2.93(1H, m), 2.92-2.81(1H, m),2.52-2.44(1H, m), 1.84-1.68(2H, m), 1.65-1.46(4H, m), 0.98(3H, d, J =6.8 Hz). 14(14e)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.47 (2H, s), 7.32(1H, s), 5.58(1H,s), 4.76-4.72 (1H, m), 4.44-4.36(2H, m), 4.17-4.07(1H, m), 3.96-3.84(2H,m), 3.65(3H, s), 3.57-3.49(1H, m), 3.04- 2.96(1H, m), 2.95-2.86(1H, m),2.52-2.44(1H, m), 1.83-1.67(2H, m), 1.64-1.44(4H, m), 0.99(3H, d, J =6.8 Hz).

TABLE 12 Example No. Structural formula Physicochemical data 14(14f)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 8.97-8.86 (1H, m), 8.45-8.32(1H, m),6.96(1H, s), 5.56(1H, s), 4.77-4.70(1H, m), 4.40-4.29(2H, m), 4.14-4.05(1H, m), 3.94-3.84(2H, m), 3.64(3H, s), 3.57-3.50(1H, m), 3.00(1H,dd, J = 16.1, 13.6 Hz), 2.93-2.82(1H, m), 2.47(1H, dd, J = 16.6, 3.9Hz), 2.16 (3H, s), 1.87-1.67(2H, m), 1.64-1.46(4H, m), 0.97(3H, d, J =6.8 Hz). 14(14g)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.29(1H, s), 5.57(1H, s),4.78-4.72(1H, m), 4.43-4.33(2H, m), 4.16-4.08(1H, m), 3.96-3.85(2H, m),3.64 (3H, s), 3.58-3.51(1H, m), 3.01(1H, dd, J = 16.1, 13.2 Hz),2.95-2.85(1H, m), 2.70(3H, s), 2.52- 2.44(1H, m), 1.85-1.68(2H, m),1.64-1.47(4H, m), 0.99(3H, d, J = 6.4 Hz). 14(14h)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.25(1H, s), 5.58(1H, s),4.33-4.23(2H, m), 4.10-3.96(2H, m), 3.65(3H, s), 3.04-2.85(2H, m),2.71(2H, s), 2.60-2.46(2H, m), 1.00(3H, d, J = 6.8 Hz). MS(ESI) m/z:435(M + H)⁺ 15(15a)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.04(1H, s), 5.56(1H, s),4.78-4.72(1H, m), 4.40-4.29(2H, m), 4.14-4.06(1H, m), 3.93-3.84(2H, m),3.64 (3H, s), 3.57-3.50(1H, m), 3.00(1H, dd, J = 16.6, 13.2 Hz),2.93-2.82(1H, m), 2.47(1H, dd, J = 16.6, 3.2 Hz), 2.08(3H, s),1.85-1.67(2H, m), 1.64-1.47(4H, m), 0.97(3H, d, J = 6.4Hz). 15(15b)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.33 (1H, s), 5.57(1H, s),4.78-4.72(1H, m), 4.45- 4.34(2H, m), 4.16-4.08(1H, m), 3.96-3.83 (2H,m), 3.54(3H, s), 3.58-3.51(1H, m), 3.00 (1H, dd, J = 16.1, 13.2Hz),2.95-2.86(1H, m), 2.54(3H, s), 2.48(1H, dd, J = 16.1 3.2 Hz),1.85-1.68(2H, m), 1.64-1.47(4H, m), 0.99(3H, d, J = 6.4 Hz).

TABLE 13 Example No. Structural formula Phsyicochemical data 15(15c)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.25(1H, s), 5.58(1H, s),4.33-4.25(2H, m), 4.09-3.98(2H, m), 3.65 (3H, s), 2.99(1H, dd, J = 16.1,13.2 Hz), 2.96-2.87(1H, m), 2.55(3H, s), 2.54 (1H, d, J = 6.4 Hz)2.50(1H, dd, J = 16.1, 3.9 Hz), 1.00 (3H, d, J = 6.4 Hz). MS(ESI) m/z:435 (M + H) ⁺ 16(16a)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.72(1H, brs), 7.16 (1H, s), 5.60(1H,s), 3.68(3H, s), 3.10- 2.85(2H, m), 2.72(3H, s), 2.59-2.43(1H, m),1.01(3H, d, J = 6.4Hz). 16(16b)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.15(1H, s), 5.58(1H, s),4.38-4.32(2H, m), 4.15-3.95(2H, m), 3.66(3H, s), 3.08-2.85(2H, m),2.74(3H, s), 2.49(1H, dd, J = 16.1, 3.9 Hz), 1.00(3H, d, J = 6.4 Hz).MS(ESI) m/z: 435 (M + H) ⁺ 17(17a)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 9.13 (1H, brd, J = 5.4 Hz), 8.59 (1H,brd, J = 5.4 Hz), 6.89 (1H, s), 5.58 (1H, s), 3.99 (3H, s), 3.63 (3H,s), 2.99 (1H, J = 16.6 13.2 Hz), 2.92-2.84 (1H, m), 2.47 (1H, dd, J =16.6, 4.4 Hz), 2.41 (2H, q, J = 7.6 Hz), 1.27 (3H, t, J = 7.6 Hz), 0.96(3H, d, J = 6.8 Hz). 17(17b)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 7.24 (1H, s), 5.58 (1H, s), 4.02 (3H,s), 3.64 (3H, s), 3.06- 2.97 (3H, m), 2.91-2.89 (1H, m), 2.48 (1H, d, J= 16.6 Hz), 1.48 (3H, t, J = 7.6 Hz), 0.99 (3H, d, J = 6.8 Hz). MS(APCl)m/z: 419 (M + H) ⁺ 18(18a)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 9.01 (1H, brd, J = 5.4 Hz), 8.51 (1H,brd, J = 5.4 Hz), 6.90 (1H, s), 5.57 (1H, s), 4.10-4.03 (2H, m), 4.00(3H, s), 3.63 (3H, s), 3.47 (2H, rd, J = 11.7, 2.4 Hz), 2.99 (1H, dd, J= 16.6, 13.2 Hz), 2.91-2.84 (1H, m), 2.64-2.52 (1H, m), 2.47 (1H, dd, J= 16.6, 4.4 Hz), 1.97-1.89 (2H, m), 1.88-1.79 (2H, m), 0.97 (3H, d, J =6.8 Hz). 18(18b)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 7.23(1H, s), 5.58 (1H, s), 4.10 (2H,td, J = 11.2, 3.9 Hz), 4.40 (3H, s), 3.64 (3H, s), 3.61 (2H, td, J =11.2, 2.6 Hz), 3.37-3.31 (1H, m), 3.01 (1H, dd, J = 16.6, 13.2 Hz),2.95-2.85 (1H, m), 2.49 (1H, dd, J = 16.6, 4.4 Hz), 2.19-2.00 (4H, m),0.99 (3H, d, J = 6.3 Hz). MS(APCl) m/z: 475 . (M + H) ⁺

TABLE 14 Example No. Structural formula Physicochemical data 19(19a)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 7.42 (1H, brs), 6.79 (1H, s), 5.56(1H, s), 4.18 (2H, brs), 3.98 (3H, s), 3.63 (3H, s), 2.99 (1H, dd, J =16.6, 13.2 Hz) 2.90-2.83 (1H, m), 2.47 (1H, dd, J = 16.6, 4.4 Hz), 0.96(3H, d, J = 6.8 Hz). 19(19b)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 7.26 (1H, s), 5.58 (1H, s), 4.03 (3H,s), 3.64 (3H, s), 3.06-2.88 (5H, m), 2.48 (1H, dd, J = 16.6, 4.4 Hz),2.34 (3H, s), 2.18-2.16 (4H, m), 2.07-2.04 (2H, m), 0.99 (3H, d, J = 6.3Hz). MS(APCl) m/z: 488 (M + H)⁺ 20

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 7.26 (1H, s), 5.58(1H, s), 4.05 (3H,s), 3.64 (3H, s), 3.00 (1H, dd, J = 16.6, 13.2 Hz), 2.94- 2.87 (1H, m),2.75-2.73 (2H, m), 2.55-2.53 (2H, m), 2.49 (1H, dd, J = 16.6, 4.4 Hz),2.46-2.39 (4H, m), 2.37 (3H, s), 0.99 (3H, d, J = 6.3 Hz). MS(APCl) m/z:506 (M + H) ⁺ 21(21a)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 9.12 (1H, d, J = 5.9 Hz), 8.74 (1H, d,J = 5.9 Hz), 6.91 (1H, s), 5.57 (1H, s), 4.01-3.96 (4H, m), 3.63 (3H,s), 3.51 (3H, s), 2.99 (1H, dd, J = 16.6, 13.2 Hz), 2.91 2.84 (1H, m),2.47 (1H, dd, J = 16.6, 4.4 Hz), 1.49 (3H, d, J = 6.8 Hz), 0.97 (3H, d,J = 6.8 Hz). 21(21b)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 7.25 (1H, s), 5.58 (1H, s), 4.78 (1H,q, J = 6.8 Hz), 4.05 (3H, s), 3.64 (3H, s), 3.46 (3H, s), 3.01 (1H, dd,J = 16.4, 13.4 Hz), 2.94-2.87 (1H, m), 2.49 (1H, dd, J = 16.6, 4.4 Hz),1.71 (3H, d, J = 6.8 Hz), 0.99 (3H, d, J = 6.8 Hz). MS(APCl) m/z: 449(M + H)⁺ 22(22a)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 7.77 (1H, brs), 7.28 (1H, s), 5.60(1H, s), 3.68 (3H, s), 3.01-2.85 (2H, m), 2.71 (3H, s), 2.61-2.47 (1H,m), 1.02 (3H, d, J = 6.3 Hz). 22(22b)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 7.20 (1H, s), 5.58 (1H, s), 4.32-4.21(2H, m), 3.64 (3H, s), 3.02 (1H, dd, J = 16.6, 13.2 Hz), 2.94-2.86 (1H,m), 2.71 (3H, s), 2.48 (1H, dd, J = 16.6, 4.4 Hz), 1.54 (3H, t, J = 7.1Hz), 1.00 (3H, d, J = 6.8 Hz). MS(APCl) m/z: 419 (M + H)⁺

TABLE 15 Example No. Structural formula Physicochemical data 23(23a)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 6.91 (1H, t, J = 73.5 Hz), 6.50 (1H,s), 5.57 (1H, s), 4.03 (3H, s), 3.64 (3H, s), 2.97 (1H, dd, J = 16.6,13.2 Hz), 2.88-2.86 (1H, m), 2.46 (1H, dd, J = 16.6, 4.4 Hz), 0.96 (3H,d, J = 6.8 Hz). MS(APCl) m/z: 389 (M + H)⁺ 23(23b)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 6.80 (1H, t, J = 72.7 Hz), 6.57 (1H,s), 5.58 (1H, s), 3.66 (3H, s), 3.00 (1H, dd, J = 16.6, 13.7 Hz),2.90-2.82 (1H, m), 2.47 (1H, dd, J = 16.6, 4.9 Hz), 0.97 (3H, d, J = 6.8Hz). 23(23c)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 6.91 (1H, s), 6.82 (1H, t, J = 72.0Hz), 5.60 (1H, s), 3.67 (3H, s), 2.98-2.84 (2H, m), 2.52 (1H, brd, J =12.2 Hz), 0.98 (3H, d, J = 6.3 Hz). 23(23d)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 7.57 (1H, s), 7.48 (2H, s), 5.85 (1H,t, J = 72.0 Hz), 5.61 (1H, s), 3.67 (3H, s), 3.04-2.87 (2H, m), 2.52(1H, brd, J = 12.2 Hz), 1.00 (3H, d, J = 6.3 Hz). 23(23e)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 9.11 (1H, s), 8.62 (1H, s), 7.18 (1H,s), 6.80 (1H, t, J = 72.2 Hz), 5.60 (1H, s), 3.66 (3H, s), 2.98-2.86(2H, m), 2.50 (1H, dd, J = 16.6, 4.4 Hz), 2.17 (3H, s), 0.97 (3H, d, J =6.3 Hz). 23(23f)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 7.53 (1H, s), 6.84 (1H, t, J = 72.0Hz), 5.60 (1H, s), 3.66 (3H, s), 3.03-2.88 (2H, m), 2.71 (3H, s), 2.52(1H, d, J = 12.7 Hz), 1.00 (3H, d, J = 6.3 Hz). MS(ESI) m/z: 441 (M +H)⁺ 24(24a)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 6.97 (1H, s), 5.57 (1H, s), 5.21 (2H,brs), 4.08 (1H, q, J = 13.2 Hz), 4.00 (3H, s), 3.63 (3H, s), 3.39 (3H,s), 3.00 (1H, dd, J = 16.6, 13.2 Hz), 2.92-2.84 (1H, m), 2.48 (1H, dd, J= 16.6, 4.4 Hz), 1.49 (3H, d, J = 6.8 Hz), 0.98 (3H, d, J = 6.3 Hz).

TABLE 16 Example No. Structural formula Physicochemical data 24(24b)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 7.29 (1H, s), 5.58 (1H, s), 4.70 (1H,q, J = 6.7 Hz), 4.05 (3H, s), 3.64 (3H, s), 3.44 (3H, s), 3.00 (1H, dd,J = 16.1, 13.2 Hz), 2.94-2.87 (1H, m), 2.49 (1H, dd, J = 16.4, 4.1 Hz),1.66 (3H, d, J = 6.7 Hz), 0.99 (3H, d, J = 6.3 Hz). MS(APCl) m/z: 449(M + H)⁺ 25(25a)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 6.93 (1H, s), 5.57 (1H, s), 5.40 (2H,brs), 3.99 (3H, s), 3.64 (3H, s), 3.00 (1H, dd, J = 16.6, 13.7 Hz),2.92-2.84 (1H, m), 2.47 (1H, dd, J = 16.4, 4.6 Hz), 2.03 (1H, s), 1.63(6H, s), 0.98 (3H, d, J = 6.3 Hz). 25(25b)

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 7.23 (1H, s), 5.58 (1H, s), 4.06 (3H,s), 3.64 (3H, s), 3.00 (1H, dd, J = 16.1, 13.2 Hz), 2.95-2.87 (1H, m),2.58 (1H, s), 2.49 (1H, dd, J = 16.4, 4.1 Hz), 1.75 (6H, s), 0.99 (3H,d, J = 6.3 Hz), MS(APCl), m/z: 449 (M + H) 26(26a)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 7.72 (1H, d, J = 2.0 Hz), 6.83 (1H, d,J = 3.2 Hz), 6.56-6.55 (1H, m), 5.61 (1H, d, J = 4.0 Hz), 5.17-5.13 (1H,m), 4.11-4.06 (1H, m), 3.97 (3H, s), 3.69 (3H, d, J = 4.8 Hz), 3.59-3.52(1H, m), 3.09-2.99 (1H, m), 2.96-2.88 (1H, m), 2.65-2.56 (1H, m),2.54-2.48 (1H, m), 2.17-2.09 (1H, m), 2.02-1.94 (1H, m), 1.82-1.71 (1H,m), 1.58-1.56 (1H, m), 1.06-1.02 (3H, m) 0.90-0.87 (1H, m). 26(26b)

¹H NMR(400 MHz, DMSO-d₆): d(ppm) = 13.42 (1H, s), 7.94 (1H, s), 7.18(1H, s), 7.00 (1H, d, J = 2.0 Hz), 5.65 (1H, s), 3.95 (3H, s), 3.65 (3H,s), 2.90-2.83 (1H, m), 2.73-2.65 (1H, m), 2.43-2.37 (1H, m), 0.85 (3H,d, J = 6.4 Hz). MS(ESI) m/z: 389 (M + H) ⁺ 27

¹H NMR(400 MHz, DMSO-d₆): d(ppm) = 7.92 (1H, d, J = 2.4 Hz), 7.13 (1H,s), 6.98 (1H, d, J = 2.4 Hz), 5.65 (1H, s), 4.39 (2H, t, J = 5.2 Hz),3.94 (3H, s), 3.75 (2H, t, J = 5.2 Hz), 3.65 (3H, s), 3.26 (3H, s),2.90-2.83 (1H, m), 2.72-2.65 (1H, m), 2.42-2.37 (1H, m), 0.85 (3H, d, J= 6.4 Hz). MS(ESI) m/z: 447 (M + H)⁺

TABLE 17 Example No. Structural formula Physicochemical data 28(28a)

¹H NMR(300 MHz, CDCl₃): δ (ppm) = 10.48 (1H, s), 7.01 (1H, s), 5.51 (1H,s), 3.95 (3H, s), 3.57 (3H, s), 3.57 (3H, s), 2.86-2.73 (1H, m),2.44-2.38 (1H, m), 2.03-1.92 (1H, m), 0.91 (3H, d, J = 6.4 Hz). 28(28b)

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 6.97 (1H, s), 5.66 (1H, s), 3.94 (3H,s), 3.83-3.74 (2H, m), 3.65 (3H, s), 3.63-3.57 (2H, s), 3.42 (2H, s),2.94-2.82 (1H, m), 2.73-2.61 (1H, m), 2.45-2.35 (1H, m), 1.88-1.80 (4H,m), 0.83 (3H, d, J = 6.8 Hz). MS(ESI) m/z: 462 (M + H) ⁺ 29

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 6.94 (1H, s), 5.57 (1H, s), 3.98 (3H,s), 3.63 (3H, s), 3.35 (2H, s), 3.07-2.98 (1H, m), 2.94-2.82 (1H, m),2.65-2.55 (4H, m), 2.47 (1H, dd, J = 16.4, 4.2 Hz), 2.36 (3H, s),2.09-2.03 (2H, m), 1.95-1.90 (2H, m), 0.97 (3H, d, J = 6.8 Hz). MS(ESI)m/z: 475 (M + H)⁺ 30

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 8.72 (2H, s), 6.48 (1H, s), 5.59 (1H,s), 4.11 (3H, s), 3.99 (3H, s), 3.66 (3H, s), 3.03 (1H, dd, J = 16.4,13.4 Hz), 2.93-2.86 (1H, m), 2.48 (1H, dd, J = 16.6, 4.4 Hz), 1.01 (3H,d, J = 6.8 Hz). MS(APCl) m/z: 431 (M + H)⁺ 31

¹H NMR(400 MHz, CDCl₃): δ (ppm) = 8.34 (1H, d, J = 2.4 Hz), 7.80 (1H,dd, J = 8.3, 2.4 Hz), 6.87 (1H, d, J = 8.3 Hz), 6.50 (1H, s), 5.58 (1H,s), 4.02 (3H, s), 3.97 (3H, s), 3.66 (3H, s), 3.04 (1H, dd, J = 16.6,13.2 Hz), 2.91-2.89 (1H, m), 2.48 (1H, m), 2.48 (1H, dd, J = 16.6, 4.4Hz), 1.02 (3H, d, J = 6.8 Hz). MS(APCl) m/z: 430 (M + H)⁺ 32

¹H NMR(500 MHz, CDCl₃): δ (ppm) = 8.77 (1H, brs), 8.72 (1H, brs),7.90-7.88 (1H, m), 7.46-7.44 (1H, m), 6.52 (1H, s), 5.59 (1H, s), 3.99(3H, s), 3.66 (3H, s), 3.05-3.02 (1H, m), 2.93-2.89 (1H, m), 2.48 (1H,dd, J = 16.4, 4.1 Hz), 1.02 (3H, d, J = 6.3 Hz). MS(APCl) m/z; 400 (M +H)+

1. A compound of a general formula (1) or a pharmacologically acceptablesalt thereof:

wherein: R¹ is a C1-C6 alkyl group optionally substituted with the sameor different one to two substituents selected from a substituent groupX, a C3-C6 cycloalkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,or a 4-7 membered saturated heterocyclic group optionally substitutedwith the same or different one to two substituents selected from thesubstituent group X, R² is a C1-C6 alkyl group optionally substitutedwith the same or different one to two substituents selected from thesubstituent group X, a C3-C6 cycloalkyl group optionally substitutedwith the same or different one to two substituents selected from thesubstituent group X, or a 4-7 membered saturated heterocyclic groupoptionally substituted with the same or different one to twosubstituents selected from the substituent group X, A is a 5-memberedaromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an8-10 membered condensed aromatic heterocyclic ring, a 5-7 memberedunsaturated heterocyclic ring, a 4-7 membered saturated heterocyclicring, a benzene ring, —CH═, or a cyano group, wherein when A is a cyanogroup, R³ and R^(3′) do not exist, R³ and R^(3′) are each independentlya hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an oxogroup, a C1-C6 alkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,a C1-C6 alkoxy group optionally substituted with the same or differentone to two substituents selected from the substituent group X, a C2-C6alkenyl group optionally substituted with the same or different one totwo substituents selected from the substituent group X, a C2-C6 alkynylgroup optionally substituted with the same or different one to twosubstituents selected from the substituent group X, a C3-C6 cycloalkylgroup optionally substituted with the same or different one to twosubstituents selected from the substituent group X, an amino groupoptionally substituted with the same or different one to twosubstituents selected from the substituent group X, a C1-C6alkoxycarbonyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X, acarbamoyl group optionally substituted with the same or different one totwo substituents selected from the substituent group X, a phenyl groupoptionally substituted with the same or different one to twosubstituents selected from the substituent group X, a 5-memberedaromatic heterocyclic group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,a 6-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup X, a 5-7 membered unsaturated heterocyclic group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group X, a 4-7 membered saturated heterocyclicgroup optionally substituted with the same or different one to twosubstituents selected from the substituent group X, an 8-10 memberedcondensed aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup X, or R³ and R^(3′) may form a 5-7 membered unsaturatedheterocyclic ring, a 4-7 membered saturated heterocyclic ring, or aC3-C6 cycloalkyl ring as a ring that binds to each other and condenseswith A, and the ring is optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,Substituent group X is a halogen atom, a cyano group, a hydroxy group,an oxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkylgroup, a C3-C6 halocycloalkyl group, a phenyl group optionallysubstituted with the same or different one to two substituents selectedfrom a substituent group Y, a 5-membered aromatic heterocyclic groupoptionally substituted with the same or different one to twosubstituents selected from the substituent group Y, a 6-memberedaromatic heterocyclic group optionally substituted with the same ordifferent one to two substituents selected from the substituent group Y,a 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, aC3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy groupoptionally substituted with the same or different one to twosubstituents selected from the substituent group Y, a 5-memberedaromatic heterocyclic oxy group optionally substituted with the same ordifferent one to two substituents selected from the substituent group Y,a 6-membered aromatic heterocyclic oxy group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y, a 4-7 membered saturated heterocyclic oxy groupoptionally substituted with the same or different one to twosubstituents selected from the substituent group Y, a C1-C6alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, a carboxygroup, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group, aphenylcarbonyl group optionally substituted with the same or differentone to two substituents selected from the substituent group Y, acarbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) amninosulfonyl group, adi (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylaminogroup, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6alkylcarbonylamino group, a phenylcarbonylamino group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group Y, a 5-membered aromatic heterocycliccarbonylamino group optionally substituted with the same or differentone to two substituents selected from the substituent group Y, a6-membered aromatic heterocyclic carbonylamino group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group Y, or a C1-C6 alkylsulfonylamino group,Substituent group Y C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenatom, or a hydroxy group, wherein a compound or a pharmaceuticallyacceptable salt thereof of the following general formula (Z) isexcluded:

wherein for the compound of general formula Z: R¹ is a C1-C6 alkyl groupor a hydroxy C1-C6 alkyl group, R² is a C1-C6 alkyl group, A is a5-membered aromatic heterocyclic ring, and R³ is a C1-C6 alkyl group, ahydroxy C1-C6 alkyl group, or a C1-C6 alkoxy C1-C6 alkyl group.
 2. Thecompound or the pharmacologically acceptable salt thereof according toclaim 1, wherein the 5-membered aromatic heterocyclic ring or the5-membered aromatic heterocyclic group in A, R³, or R³ is any oneselected from the group:


3. The compound or the pharmacologically acceptable salt thereofaccording to claim 1, wherein the 6-membered aromatic heterocyclic ringor the 6-membered aromatic heterocyclic group in A, R³, or R^(3′) is anyone selected from the group:


4. The compound or the pharmacologically acceptable salt thereofaccording to claim 1, wherein the 8-10 membered condensed aromaticheterocyclic ring or the 8-10 membered condensed aromatic heterocyclicgroup in A, R³, or R^(3′) is any one selected from the group:


5. The compound or the pharmacologically acceptable salt thereofaccording to claim 1, wherein the 5-7 membered unsaturated heterocyclicring or 5-7 membered unsaturated heterocyclic group in A, R³, or R^(3′)is any one selected from the group:


6. The compound or the pharmacologically acceptable salt thereofaccording to claim 1, to wherein the 4-7 membered saturated heterocyclicring or the 4-7 membered saturated heterocyclic group in A, R¹, R², orR³ is any one selected from the group:


7. The compound or the pharmacologically acceptable salt thereofaccording to claim 1, wherein the compound of the general formula (1) isany compound selected from the following group:(2S,5′R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-4-ethoxy-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-4-(difluoromethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione; (2S,5′R)-7-chloro-6-[3-(I-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione; (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(1H-pyrazol-5-yl) spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl) Spiro [benzofuran-2,4′-cyclohex-2-ene]-1,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione; (2S,‘’R)-7-chloro-3′,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione; or(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(3-pyridyl) spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione.
 8. A pharmaceuticalcomposition containing the compound or the pharmacologically acceptablesalt thereof, according to claim 1, as an active ingredient.
 9. A methodfor preventing and/or treating a central inflammatory disease in asubject in need thereof, comprising administering to the subject thepharmaceutical composition according to claim 8, thereby treating thecentral inflammatory disease.
 10. A pharmaceutical composition for theprevention and/or treatment of a central inflammatory disease, thepharmaceutical composition containing a compound of a general formula(1′) or a pharmacologically acceptable salt thereof;

wherein: R¹ is a C1-C6 alkyl group optionally substituted with the sameor different one to two substituents selected from the substituent groupX, a C3-C6 cycloalkyl group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,or a 4-7 membered saturated heterocyclic group optionally substitutedwith the same or different one to two substituents selected from thesubstituent group X R² is a C1-C6 alkyl group optionally substitutedwith the same or different one to two substituents selected from thesubstituent group X, a C3-C6 cycloalkyl group optionally substitutedwith the same or different one to two substituents selected from thesubstituent group X, or a 4-7 membered saturated heterocyclic groupoptionally substituted with the same or different one to twosubstituents selected from the substituent group X. A is a 5-memberedaromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an8-10 membered condensed aromatic heterocyclic ring, a 5-7 memberedunsaturated heterocyclic ring, a 4-7 membered saturated heterocyclicring, a benzene ring, or a single bond, wherein (when it is a singlebond, one or the other of R³ and R^(3′) is not present, R³ and R^(3′)are each independently a hydrogen atom, a halogen atom, a cyano group, ahydroxy group, a C1-C6 alkyl group optionally substituted with the sameor different one to two substituents selected from the substituent groupX, a C1-C6 alkoxy group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,a C2-C6 alkenyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X, a C2-C6alkynyl group optionally substituted with the same or different one totwo substituents selected from the substituent group X, a C3-C6cycloalkyl group optionally substituted with the same or different oneto two substituents selected from the substituent group X, an aminogroup optionally substituted with the same or different one to twosubstituents selected from the substituent group X, a C1-C6alkoxycarbonyl group optionally substituted with the same or differentone to two substituents selected from the substituent group X, acarbamoyl group optionally substituted with the same or different one totwo substituents selected from the substituent group X, a phenyl groupoptionally substituted with the same or different one to twosubstituents selected from the substituent group X, a 5-memberedaromatic heterocyclic group optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,a 6-membered aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup X, a 5-7 membered unsaturated heterocyclic group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group X, a 4-7 membered saturated heterocyclicgroup optionally substituted with the same or different one to twosubstituents selected from the substituent group X, an 8-10 memberedcondensed aromatic heterocyclic group optionally substituted with thesame or different one to two substituents selected from the substituentgroup X, or R³ and R^(3′) may form a 5-7 membered unsaturatedheterocyclic ring, a 4-7 membered saturated heterocyclic ring, or aC3-C6 cycloalkyl ring as a ring that binds to each other and condenseswith A, and the ring is optionally substituted with the same ordifferent one to two substituents selected from the substituent group X,Substituent group X is halogen atom, a cyano group, a hydroxy group, anoxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkylgroup, a C3-C6 halocycloalkyl group, a phenyl group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group Y, a 5-membered aromatic heterocyclic groupoptionally substituted with the same or different one to twosubstituents selected from the substituent group Y, a 6-memberedaromatic heterocyclic group optionally substituted with the same ordifferent one to two substituents selected from the substituent group Y,a 4-7 membered saturated heterocyclic group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, aC3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy groupoptionally substituted with the same or different one to twosubstituents selected from the substituent group Y, a 5-memberedaromatic heterocyclic oxy group optionally substituted with the same ordifferent one to two substituents selected from the substituent group Y,a 6-membered aromatic heterocyclic oxy group optionally substituted withthe same or different one to two substituents selected from thesubstituent group Y, a 4-7 membered saturated heterocyclic oxy groupoptionally substituted with the same or different one to twosubstituents selected from the substituent group Y, a C1-C6alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, a carboxygroup, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group, aphenylcarbonyl group optionally substituted with the same or differentone to two substituents selected from the substituent group Y, acarbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, adi (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylaminogroup, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6alkylcarbonylamino group, a phenylcarbonylamino group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group Y, a 5-membered aromatic heterocycliccarbonylamino group optionally substituted with the same or differentone to two substituents selected from the substituent group Y, a6-membered aromatic heterocyclic carbonylamino group optionallysubstituted with the same or different one to two substituents selectedfrom the substituent group Y, or a C1-C6 alkylsulfonylamino group, andSubstituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, ahalogen atom, or a hydroxy group.
 11. The pharmaceutical compositionaccording to claim 10, wherein R¹ is a methyl group, an ethyl group, ora hydroxyethyl group.
 12. The pharmaceutical composition according toclaim 10, wherein R² is a methyl group.
 13. The pharmaceuticalcomposition according to claim 10, wherein the 5-membered aromaticheterocyclic ring or the 5-membered aromatic heterocyclic group in A,R³, or R^(3′) is any one selected from the group:


14. The pharmaceutical composition according to claim 10, wherein the6-membered aromatic heterocyclic ring or the 6-membered aromaticheterocyclic group in A, R³, or R^(3′) is any one selected from thegroup:


15. The pharmaceutical composition according to claim 10, wherein the5-7 membered unsaturated heterocyclic ring or the 5-7 memberedunsaturated heterocyclic group in A, R³, or R^(3′) is any one selectedfrom the group:


16. The pharmaceutical composition according to claim 10, wherein the4-7 membered saturated heterocyclic ring or the 4-7 membered saturatedheterocyclic group in A, R¹, R², or R³ is any one selected from thegroup:


17. The pharmaceutical composition according to claim 10, wherein A is a5-membered aromatic heterocyclic ring, R³ is a methyl group, an ethylgroup, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group, andR^(3′) is a hydrogen atom.
 18. The pharmaceutical composition accordingto claim 10, wherein A is any ring selected from the following group,and in the case of two binding groups, R^(3′) is not present:

wherein * indicates a binding group.
 19. A pharmaceutical compositionfor the prevention and/or treatment of a central inflammatory disease,the pharmaceutical composition containing a compound of a generalformula (1″) or a pharmacologically acceptable salt thereof:

wherein R¹ is a methyl group or an ethyl group; R² is a methyl group; Ais any ring selected from the following group

indicates a binding group; and R³ is a methyl group or an ethyl group.20. The pharmaceutical composition according to claim 10, wherein thecompound of the general formula (1′) is any compound selected from thefollowing group:(2S,5′R)-7-chloro-6-(2-hydroxyethoxy)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-6-(2-methoxyethoxy)-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(1-methylpyrazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl)-1,2,4-oxadiazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione(2S,5′R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-6-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3′-methoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-4-ethoxy-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3′-methoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione; (2S,5′R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione; (2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-4-(2-hydroxyethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione; (2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione; (2S,5′R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-6-[5-[(lS)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-4-ethoxy-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione; (2S,5′R)-7-chloro-4-(difluoromethoxy)-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)Spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3′-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(1H-pyrazol-5-yl) spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl) Spiro [benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione; (2S,5′R)-7-chloro-3′,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione;(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(3-pyridyl) Spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione; or(2,5′R)-7-chloro-3′,4,6-trimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione.
 21. The pharmaceuticalcomposition according to claim 20 for the prevention and/or treatment ofa central inflammatory disease, the pharmaceutical compositioncontaining a compound (2S,5′R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′ 3-dione or a pharmacologicallyacceptable salt thereof.
 22. The pharmaceutical composition according toclaim 20 for the prevention and/or treatment of a central inflammatorydisease, the pharmaceutical composition containing a compound(2S,5′R)-7-chloro-3′,4-dimethoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione or a pharmacologicallyacceptable salt thereof.
 23. The pharmaceutical composition according toclaim 20 for the prevention and/or treatment of a central inflammatorydisease, the pharmaceutical composition containing a compound(2S,5′R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione or a pharmacologicallyacceptable salt thereof.
 24. The pharmaceutical composition according toclaim 20 for the prevention and/or treatment of a central inflammatorydisease, the pharmaceutical composition containing a compound(2S,5′R)-7-chloro-6-[3-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3′,4-dimethoxy-5′-methyl-spiro[benzofuran-2,4′-cyclohex-2-ene]-1′,3-dione or a pharmacologicallyacceptable salt thereof.
 25. The pharmaceutical composition according toclaim 20 for the prevention and/or treatment of a central inflammatorydisease, the pharmaceutical composition containing a compound(2S,5′R)-7-chloro-4-ethoxy-3′-methoxy-5′-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro [benzofuran-24′-cyclohex-2-ene]-1′,3-dione or a pharmacologicallyacceptable salt thereof.
 26. The method according to claim 9, whereinthe central inflammatory disease is any one selected from a groupconsisting of Alzheimer's disease, Parkinson's disease, Lewy bodydementia, multiple system atrophy, Pick's disease, progressivesupranuclear palsy, cerebral cortex basement degeneration,frontotemporal lobe degeneration, Huntington's disease, amyotrophiclateral sclerosis, spinal and bulbar muscular atrophy, spinal muscularatrophy, spinocerebellar degeneration, multiple sclerosis,Creutzfeldt-Jakob disease, fatal familial insomnia,Gerstmann-Straussler-Scheinker syndrome, Down syndrome, Niemann-Pickdisease, cerebral amyloid angiopathy, HIV encephalopathy, influenzaencephalopathy, hepatic encephalopathy, progressive multifocalleukoencephalopathy, anti-NMDA receptor antibody encephalitis,cerebrovascular disorders, traumatic brain injuries, spinal cordinjuries, hypoxic encephalopathy, epilepsy, optic neuritis, congenitalmetabolic brain diseases, Wernicke's encephalopathy, autism spectrumdisorders, attention deficit/hyperactivity disorders, tic disorders,schizophrenia, bipolar disorders, major depressive disorders (treatmentresistant depression and postpartum depression), persistent depressivedisorders (dysthymic disorder), premenstrual dysthymic disorders,anxiety disorders, focal phobia, panic disorders, obsessive compulsivedisorders, emotional trauma and stress related disorders, eatingdisorders, circadian rhythm sleep/wake disorders, narcolepsy, substancerelated disorders (alcohol addiction and drug addiction), impulsecontrol disorders, delirium, personality disorders, and Rett's syndrome.27. The method according to claim 9, wherein the central inflammatorydisease is any one selected from a group consisting of Alzheimer'sdisease, Parkinson's disease, Lewy body dementia, multiple systematrophy, Pick's disease, progressive supranuclear palsy, cerebral cortexbasement degeneration, frontotemporal lobe degeneration, Huntington'sdisease, amyotrophic lateral sclerosis, spinal and bulbar muscularatrophy, spinal muscular atrophy, spinocerebellar degeneration, multiplesclerosis, Creutzfeldt-Jakob disease, schizophrenia, bipolar disorders,major depressive disorders (treatment resistant depression andpostpartum depression), persistent depressive disorders (dysthymicdisorder), premenstrual dysthymic disorders, anxiety disorders, focalphobia, panic disorders, obsessive compulsive disorders, emotionaltrauma and stress related disorders, eating disorders, circadian rhythmsleep/wake disorders, narcolepsy, substance related disorders (alcoholaddiction and drug addiction), impulse control disorders, delirium,personality disorders, and Rett's syndrome
 28. The method according toclaim 9, wherein the central inflammatory disease is any one selectedfrom a group consisting of schizophrenia, bipolar disorders, majordepressive disorders (treatment resistant depression and postpartumdepression), persistent depressive disorders (dysthymic disorder),premenstrual dysthymic disorders, anxiety disorders, focal phobia, panicdisorders, and obsessive compulsive disorders. 29-36. (canceled)